{"drugbank_id":"DB00112","indication":"As a vascular endothelial growth factor (VEGF) inhibitor, bevacizumab is used in several chemotherapy regimens to treat metastatic colorectal cancer; metastatic, unresectable, locally advanced or recurrent non-squamous non-small cell lung cancer; metastatic renal cell carcinoma; metastatic, persistent, or recurrent cervical cancer; primary peritoneal cancer; epithelial ovarian cancer; and fallopian tube cancer.[L12648] It can also be used to treat recurrent glioblastoma.[L12648]\r\n\r\nInterestingly, bevacizumab is currently under investigation for the treatment of COVID-19 complications including acute respiratory distress syndrome (ARDS) and acute lung injury (ALI).[L12699]","pharmacodynamics":"Bevacizumab binds circulating vascular endothelial-derived growth factor (VEGF) and blocks it from binding to its associated receptors, effectively blunting downstream signaling.[A192963] The effects of bevacizumab have been shown to re-establish normal vasculature at the tumor site resulting in increased nutrient and oxygen supply, while also improving the delivery of chemotherapeutic drugs to the target area.[A192939,A192960] On the other hand, VEGF signaling is a vital component of several processes including angiogenesis, lymphangiogenesis, blood pressure regulation, wound healing, coagulation, and renal filtration.[A192834,A192888,A192963] Although blocking VEGF may inhibit metastatic disease progression, it may also result in unintended effects due to the role of VEGF in several other physiologic processes.[L12648]","mechanism_of_action":"Transcription of the VEGF protein is induced by 'hypoxia inducible factor' (HIF) in a hypoxic environment.[A192939] When circulating VEGF binds to VEGF receptors (VEGFR-1 and VEGFR-2) located on endothelial cells, various downstream effects are initiated.[A192834,A192939] It should be noted that VEGF also binds to the neuropilin co-receptors (NRP-1 and NRP-1), leading to enhanced signaling.[A192939,A192951] \r\n\r\nCancer cells promote tumor angiogenesis by releasing VEGF, resulting in the creation of an immature and disorganized vascular network.[A192894,A192897] The hypoxic microenvironment promoted by cancer cells favors the survival of more aggressive tumor cells, and gives rise to a challenging environment for immune cells to respond appropriately.[A192897,A192900,A192903] As a result, VEGF has become a well-known target for anti-cancer drugs like bevacizumab.[A192837] Bevacizumab is a mAb that exerts its effects by binding and inactivating serum VEGF.[A192939] When bound to the mAb, VEGF is unable to interact with its cell surface receptors, and proangiogenic signalling is inhibited.[A192939] This prevents formation of new blood vessels, decreases tumor vasculature, and reduces tumor blood supply.[A192939,L12648] \r\n\r\nThere is also evidence to suggest that VEGF is upregulated in COVID-19 patients, hence, bevacizumab is being investigated for the treatment of associated complications.[L12699] Higher levels of VEGF may contribute to pulmonary edema, leading to acute respiratory distress syndrome (ARDS) and acute lung injury (ALI).[L12699] Researchers are hopeful that by inhibiting VEGF, bevacizumab may effectively treat ARDS and ALI - both common features of severe COVID-19 cases.[L12699]","toxicity":"Bevacizumab toxicities are distinct from the effects of cytotoxic agents used in chemotherapy, and are normally linked to impaired VEGF function.[A192960,A192963] Common toxicities associated with bevacizumab include hypertension, gastrointestinal perforation, arterial thromboembolism, reversible posterior leukoencephalopathy syndrome (RPLS), venous thromboembolism, proteinuria, bleeding/hemorrhage, and wound-healing complications.[A192960]","metabolism":"There are several pathways through which monoclonal antibodies (mAbs) may be cleared.[A192948] Non-specific clearance of mAbs refers to target independent pinocytosis, and proteolysis of the protein into small amino acids and peptides in the reticuloendothelial system (RES) and the liver.[A192948,A40006] Target-mediated clearance is a result of specific interactions between the mAb and its target antigen.[A192948] Once bound, the antibody-antigen complex may be cleared via lysosomal degradation.[A192948,A40006] Additionally, the production of anti-drug antibodies (ADA), which are a result of an immunogenic response to mAb-based treatment, can form complexes with mAb\u001as and may impact the rate of mAb clearance.[A192948]","absorption":"Monoclonal antibodies (mAbs) are large in size, do not readily cross cell membranes, and are unable to withstand proteolysis in the gastrointestinal tract.[A40006,A192981,A19126] Given these characteristics, mAbs are poorly absorbed via the oral route and are instead administered intravenously, intramuscularly or subcutaneously.[A40006,A19126]\r\n\r\nIn a single dose (1mg/kg) pharmacokinetic study assessing the bioequivalence of bevacizumab and TAB008 (a biosimilar product), the pharmacokinetic parameters of Avastin (bevacizumab) were as follows[A192975]:\r\nGeometric mean Cmax = 17.38 ug/mL\r\nGeometric mean AUCinf = 5,358 ugxh/mL\r\nGeometric mean Tmax = 2.50 hrs\r\n","half_life":"The half-life of bevacizumab is estimated to be 20 days (range of 11-50 days).[L12648,A192921]","protein_binding":">97% of serum VEGF is bound to bevacizumab.[A192939]","route_of_elimination":"Due to their size, monoclonal antibodies are not renally eliminated under normal physiological conditions.[A40006] Catabolism or excretion are the primary processes of elimination.[A40006]","volume_of_distribution":"The volume of distribution of bevacizumab is approximately 3.29 L and 2.39 L for the average male and female, respectively.[A192939]","clearance":"The clearance (CL) of bevacizumab is approximately 0.207 L/day.[A192939] The CL of bevacizumab can increase or decrease by 30% in patients who weigh >114 kg or <49 kg respectively.[A192939] Males tend to clear bevacizumab at a faster rate than females (26% faster on average).[A192939] Other factors including alkaline phosphatase (ALP), serum aspartate aminotransferase (AST), serum albumin, and tumor burden may cause the CL to fluctuate.[A192939]\r\n"}
{"drugbank_id":"DB00207","indication":"Azithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria in order to prevent the development antimicrobial resistance and maintain the efficacy of azithromycin [FDA label].\r\n\r\nAzithromycin is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the microorganisms listed in the specific conditions below. Recommended dosages, duration of therapy and considerations for various patient populations may vary among these infections. Refer to the FDA label and \"Indications\" section of this drug entry for detailed information [FDA label]. \r\n\r\n**Adults**:\r\n\r\nAcute bacterial exacerbations of chronic obstructive pulmonary disease due to _Haemophilus influenzae_, _Moraxella catarrhalis_ or _Streptococcus pneumoniae_\r\n\r\nAcute bacterial sinusitis due to _Haemophilus influenzae_, _Moraxella catarrhalis_ or _Streptococcus pneumoniae_\r\n\r\nCommunity-acquired pneumonia due to _Chlamydophila pneumoniae_, _Haemophilus influenzae_, _Mycoplasma pneumoniae_ or _Streptococcus pneumoniae_ in patients appropriate for oral therapy\r\n\r\nPharyngitis/tonsillitis caused by _Streptococcus pyogenes_ as an alternative to first-line therapy in individuals who cannot use first-line therapy.\r\nUncomplicated skin and skin structure infections due to _Staphylococcus aureus_, _Streptococcus pyogenes_, or _Streptococcus agalactiae_. Abscesses usually require surgical drainage.\r\n\r\nUrethritis and cervicitis due to _Chlamydia trachomatis_ or _Neisseria gonorrhoeae_.\r\n\r\nGenital ulcer disease in men due to _Haemophilus ducreyi_ (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established.\r\n\r\n**Pediatric Patients**\r\n\r\nAcute otitis media caused by _Haemophilus influenzae_, _Moraxella catarrhalis_ or _Streptococcus pneumoniae_\r\n\r\nCommunity-acquired pneumonia due to _Chlamydophila pneumoniae_, _Haemophilus influenzae_, _Mycoplasma pneumoniae_ or _Streptococcus pneumoniae_ in patients appropriate for oral therapy.\r\n\r\nPharyngitis/tonsillitis caused by _Streptococcus pyogenes_ as an alternative to first-line therapy in individuals who cannot use first-line therapy.","pharmacodynamics":"Macrolides stop bacterial growth by inhibiting protein synthesis and translation, treating bacterial infections [A174175].\r\nAzithromycin has additional immunomodulatory effects and has been used in chronic respiratory inflammatory diseases for this purpose [A174172].\r\n\r\n","mechanism_of_action":"In order to replicate, bacteria require a specific process of protein synthesis, enabled by ribosomal proteins [A6505]. Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit. It stops bacterial protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit [FDA label], [A14179]. This results in the control of various bacterial infections [A174193], [FDA label].   The strong affinity of macrolides, including azithromycin, for bacterial ribosomes, is consistent with their broad\u001aspectrum antibacterial activities [A174193].\r\n\r\n\r\nAzithromycin is highly stable at a low pH, giving it a longer serum half-life and increasing its concentrations in tissues compared to erythromycin [A174175]. \r\n\r\n","toxicity":"**Rat Oral LD50**: >2000 mk/kg [MSDS]\r\n\r\nPossible major adverse effects include cardiovascular arrhythmias and hearing loss. Macrolide resistance is also an ongoing issue [A174172]. Hepatotoxicity has been since in rare cases [A174175]. \r\n\r\n**A note on the risk of liver toxicity**:\r\n\r\nDue to the act that  azithromycin is mainly eliminated by the liver, caution should be observed when azithromycin is given to patients with decreased hepatic function [FDA label]. \r\n\r\n**A note on potential renal toxicity**:\r\n\r\nBecause limited data in patients with renal GFR <10 mL/min, caution should be exercised when prescribing azithromycin to these patients [FDA label].\r\n\r\n**Use in Pregnancy**:\r\n\r\nThis drug is categorized as a pregnancy category B drug. Reproduction studies have been done in rats and mice at doses up to moderately maternally toxic doses (for example, 200 mg/kg/day). These doses, based on a mg/m2 basis, are approximately 4 and 2 times, respectively, the human daily dose of 500 mg. In the animal studies, no harmful effects to the fetus due to azithromycin were observed. There are, at this time, no conclusive and well-controlled studies that have been done in pregnant women. Because animal reproduction studies do not always predict human response, azithromycin should be used during pregnancy only if clearly needed [FDA label].\r\n\r\n**Nursing Mothers**: \r\n\r\nIt is unknown at this time whether azithromycin is excreted in human milk. Because many other drugs are excreted in human milk, caution should be observed when azithromycin is given to a nursing woman [FDA label].\r\n\r\n**Carcinogenesis, Mutagenesis, Impairment of Fertility**: \r\n\r\nLong-term studies in animals have not been performed to study carcinogenic potential. Azithromycin has demonstrated no potential to be mutagenic in standard laboratory tests. No evidence of negative effects on fertility due to azithromycin was found [FDA label].","metabolism":"In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed [FDA label], however, this drug is eliminated by the liver [A174202], [FDA label].","absorption":"Bioavailability of azithromycin is 37% following oral administration. Absorption is not affected by food.  Macrolide absorption in the intestines is believed to be mediated by P-glycoprotein (ABCB1) efflux transporters, which are known to be encoded by the _ABCB1_ gene [A174175].","half_life":"Terminal elimination half-life: 68 hours [FDA label]","protein_binding":"The serum protein binding of azithromycin varies in humans, decreasing from 51% at 0.02 g/mL to 7% at 2 g/mL [FDA label].","route_of_elimination":"Biliary excretion of azithromycin, primarily as unchanged drug, is a major route of elimination. Over a 1 week period, approximately 6% of the administered dose is found as unchanged drug in urine [FDA label].","volume_of_distribution":"After oral administration, azithromycin is widely distributed in tissues with an apparent steady-state volume of distribution of 31.1 L/kg [FDA label].  Significantly greater azithromycin concentrations have been measured in the tissues rather than in plasma or serum  [FDA label], [A174172]. The lung, tonsils and prostate are organs have shown a particularly high rate of azithromycin uptake [A174172].\r\n\r\nThis drug is concentrated within macrophages and polymorphonucleocytes, allowing for effective activity against Chlamydia trachomatis [A174175]. In addition, azithromycin is found to be concentrated in phagocytes and fibroblasts, shown by in vitro incubation techniques. In vivo studies demonstrate that concentration in phagocytes may contribute to azithromycin distribution to inflamed tissues [FDA label].","clearance":"Mean apparent plasma cl=630 mL/min (following single 500 mg oral and i.v. dose) [FDA label]"}
{"drugbank_id":"DB00503","indication":"Indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.","pharmacodynamics":"Ritonavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Ritonavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. Modern protease inhibitors require the use of low-dose ritonavir to boost pharmacokinetic exposure through inhibition of metabolism via the cytochrome P450 3A4 enzyme pathway.","mechanism_of_action":"Ritonavic inhibits the HIV viral proteinase enzyme that normally cleaves the structural and replicative proteins that arise from major HIV genes, such as *gag* and *pol*. *Gag* encodes proteins involved in the core and the nucleocapsid, while *pol* encodes the the HIV reverse transcriptase, ribonuclease H, integrase, and protease [A19647]. The *pol*-encoded proteins are initially translated in the form of a larger precursoe polypeptide, *gag-pol*, and needs to be cleaved by HIV protease to form other complement proteins [A19647]. Ritonavir prevents the cleavage of the *gag-pol* polyprotein, which results in noninfectious, immature viral particles. Ritonavir is a potent inhibitor of cytochrome P450 CYP3A4 isoenzyme present both in the intestinal tract and liver [A19647]. It is a type II ligand that perfectly fits into the CYP3A4 active site cavity and irreversibly binds to the heme iron via the thiazole nitrogen, which decreases the redox potential of the protein and precludes its reduction with the redox partner, cytochrome P450 reductase [A19648]. Ritonavir may also play a role in limiting cellular transport and efflux of other protease inhibitors via the P-glycoprotein and MRP efflux channels [A19647].","toxicity":"Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose. The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice. Oral LD value in rats is >2500 mg/kg. Adverse effects of ritonavir may arise from drug-drug interactions. Other effects include hepatotoxicity, pancreatitis, and allergic reactions/hypersensitivity.","metabolism":"Ritonavir circulates in the plasma predominantly as unchanged drug. Five metabolites have been identified.[L3513] The isopropylthiazole oxidation metabolite (M-2) is the major metabolite in low plasma concentrations and retains similar antiviral activity to unchanged ritonavir. The cytochrome P450 enzymes CYP3A and CYP2D6 are the enzymes primarily involved in the metabolism of ritonavir.[L3513]","absorption":"The absolute bioavailability of ritonavir has not been determined.[L3513] Following oral administration, peak concentrations are reached after approximately 2 hours and 4 hours (T<sub>max<\/sub>) after dosing under fasting and non-fasting conditions, respectively.[L3513] It should be noted that ritonavir capsules and tablets are not considered bioequivalent.[L3513]","half_life":"The approximate half-life of ritonavir is 3-5 hours.[L3513]","protein_binding":"Ritonavir is highly protein-bound in plasma (~98-99%), primarily to albumin and alpha-1 acid glycoprotein over the standard concentration range.[L3513]","route_of_elimination":"Ritonavir is primarily eliminated in the feces.[L3513] Following oral administration of a single 600mg dose of radiolabeled ritonavir, approximately 11.3 \u001a 2.8% of the dose was excreted into the urine, of which 3.5 \u001a 1.8% was unchanged parent drug.[L3513] The same study found that 86.4 \u001a 2.9% of the dose was excreted in the feces, of which 33.8 \u001a 10.8% was unchanged parent drug.[L3513]","volume_of_distribution":"The estimated volume of distribution of ritonavir is 0.41 \u001a 0.25 L/kg.[L3513]","clearance":"The apparent oral clearance at steady-state is 8.8 \u001a 3.2 L/h.[L3513] Renal clearance is minimal and estimated to be <0.1 L/h.[L3513]"}
{"drugbank_id":"DB00608","indication":"Chloroquine is indicated to treat infections of _P. vivax_, _P. malariae_, _P. ovale_, and susceptible strains of _P. falciparum_.[L12051] It is also used to treat extraintestinal amebiasis.[L12051]\r\n\r\nChloroquine is also used off label for the treatment of rheumatic diseases,[A191655] as well as treatment and prophylaxis of Zika virus.[A191649,A191652] Chloroquine is currently undergoing clinical trials for the treatment of COVID-19.[A191631]","pharmacodynamics":"Chloroquine inhibits the action of heme polymerase, which causes the buildup of toxic heme in _Plasmodium_ species.[A191700] It has a long duration of action as the half life is 20-60 days.[A191676] Patients should be counselled regarding the risk of retinopathy with long term usage or high dosage, muscle weakness, and toxicity in children.[L12051]","mechanism_of_action":"Chloroquine inhibits the action of heme polymerase in malarial trophozoites, preventing the conversion of heme to hemazoin.[A191700,A183080,A191781] _Plasmodium_ species continue to accumulate toxic heme, killing the parasite.[A191700]\r\n\r\nChloroquine passively diffuses through cell membranes and into endosomes, lysosomes, and Golgi vesicles; where it becomes protonated, trapping the chloroquine in the organelle and raising the surrounding pH.[A191676,A191628] The raised pH in endosomes, prevent virus particles from utilizing their activity for fusion and entry into the cell.[A191625]\r\n\r\nChloroquine does not affect the level of ACE2 expression on cell surfaces, but inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry.[A191628,A191625] ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry.[A191625]","toxicity":"Patients experiencing an overdose may present with headache, drowsiness, visual disturbances, nausea, vomiting, cardiovascular collapse, shock, convulsions, respiratory arrest, cardiac arrest, and hypokalemia.[L12051] Overdose should be managed with symptomatic and supportive treatment which may include prompt emesis, gastric lavage, and activated charcoal.[L12051]","metabolism":"Chloroquine is N-dealkylated primarily by CYP2C8 and CYP3A4 to N-desethylchloroquine.[A38847,A191661,A39300,A191676] It is N-dealkylated to a lesser extent by CYP3A5, CYP2D6, and to an ever lesser extent by CYP1A1.[A38847,A191661,A39300,A191676] N-desethylchloroquine can be further N-dealkylated to N-bidesethylchloroquine, which is further N-dealkylated to 7-chloro-4-aminoquinoline.[A191676]","absorption":"Chloroquine oral solution has a bioavailability of 52-102% and oral tablets have a bioavailability of 67-114%.[A191676] Intravenous chloroquine reaches a C<sub>max<\/sub> of 650-1300\u001ag/L and oral chloroquine reaches a C<sub>max<\/sub> of 65-128\u001ag/L with a T<sub>max<\/sub> of 0.5h.[A191676]","half_life":"The half life of chloroquine is 20-60 days.[A191676]","protein_binding":"Chloroquine is 46-74% bound to plasma proteins.[A191673] (-)-chloroquine binds more strongly to alpha-1-acid glycoprotein and (+)-chloroquine binds more strongly to serum albumin.[A191667]","route_of_elimination":"Chloroquine is predominantly eliminated in the urine.[A191676] 50% of a dose is recovered in the urine as unchanged chloroquine, with 10% of the dose recovered in the urine as desethylchloroquine.[A191676]","volume_of_distribution":"The volume of distribution of chloroquine is 200-800L/kg.[A191676]","clearance":"Chloroquine has a total plasma clearance of 0.35-1L/h/kg.[A191676]"}
{"drugbank_id":"DB00959","indication":"Oral and intramuscular methylprednisolone are indicated for a number of endocrine,  rheumatic, collagen, dermatologic, allergic, ophthalmic, respiratory, hematologic, neoplastic, edematous, gastrointestinal, nervous system, and other disorders.[L10785,L10788] Intra-articular and soft tissue injections are indicated for short term treatment of acute gouty arthritis, acute and subactute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, and synovitis of osteoarthritis.[L10788] Intralesional injections are indicated for alopecia areata, discoid lupus erythematosus, keloids, lichen planus, lichen simplex chronicus and psoriatic plaques, necrobiosis lipoidica diabeticorum, and localized hypertrophic infiltrated inflammatory lesions of granuloma annulare.[L10788]","pharmacodynamics":"Corticosteroids bind to the glucocorticoid receptor, inhibiting pro-inflammatory signals, and promoting anti-inflammatory signals.[A187463] Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces.[A187463] Patients taking corticosteroids should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections.[A187463]","mechanism_of_action":"The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation.[A187463] Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days.[A187463]\r\n\r\nGlucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10.[A187463]\r\n\r\nLower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive.[A187463] High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels.[A187463]","toxicity":"The oral LD<sub>50<\/sub> in rats is >4g/kg.[L10824] The intraperitoneal LD<sub>50<\/sub> in mice is 2292mg/kg and in rats is 100mg/kg.[L10824]\r\n\r\nData regarding acute overdoses of glucocorticoids are rare.[L10785,L10788] Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency.[A188405] Treat acute overdoses with symptomatic and supportive therapy, while chronic overdoses will require temporarily reduced dosages.[A188405,L10788]","metabolism":"The metabolism of methylprednisolone is thought to be mostly mediated by 11beta-hydroxysteroid dehydrogenases and 20-ketosteroid reductases.[A188757]","absorption":"Oral methylprednisolone has 89.9% the bioavailability of oral methylprednisolone acetate, while rectal methylprednisolone has 14.2% the bioavailability.[A188802] Intravitreal methylprednisolone has a T<sub>max<\/sub> of 2.5h.[A188808] Approximately 1/10 of an oral or IV dose of methylprednisolone will reach the vitreous humor.[A188808] Further data regarding the absorption of methylprednisolone are not readily available.[L10785,L10788]","half_life":"Methylprednisolone has a half life of 2.3h.[A188757,A188802]","protein_binding":"Methylprednisolone is 76.8% protein bound in plasma and does not significantly bind to corticosteroid binding protein.[A188757] Methylprednisolone is bound to human serum albumin in plasma.[A187147]","route_of_elimination":"Methylprednisolone and its metabolites have been collected in urine in humans.[A188766] A study in dogs showed 25-31% elimination in urine and 44-52% elimination in feces.[A188799]","volume_of_distribution":"The average volume of distribution of methylprednisolone is 1.38L/kg.[A188757]","clearance":"The average plasma clearance of methylprednisolone is 336mL/h/kg.[A188757]"}
{"drugbank_id":"DB01050","indication":"Ibuprofen is the most commonly used and prescribed NSAID. It is very common over the counter medication widely used as an analgesic, anti-inflammatory and antipyretic.[A39096]\r\n\r\nThe use of ibuprofen and its enantiomer [DB09213] in a racemic mix is common for the management of mild to moderate pain related to dysmenorrhea, headache, migraine, postoperative dental pain, spondylitis, osteoarthritis, rheumatoid arthritis, and soft tissue disorder.[A39097]\r\n\r\nDue to its activity against prostaglandin and thromboxane synthesis, ibuprofen has been attributed to alteration of platelet function and prolongation of gestation and labor.[A39092]\r\n\r\nAs ibuprofen is a widely used medication, the main therapeutic indications are:\r\n\r\n* Patent Ductus Arteriosus - it is a neonatal condition wherein the ductus arteriosus (blood vessel that connects the main pulmonary artery to the proximal descending aorta) fails to close after birth causing severe risk of heart failure. The prostaglandin inhibition of ibuprofen has been studied for the treatment of this condition as it is known that prostaglandin E2 is responsible for keeping the ductus arteriosus open.[A39100]\r\n\r\n* Rheumatoid- and osteo-arthritis - ibuprofen is very commonly used in the symptomatic treatment of inflammatory, musculoskeletal and rheumatic disorders.[A39176]\r\n\r\n* Cystic fibrosis - the use of high dosages of ibuprofen has been proven to decrease inflammation and decreasing polymorphonuclear cell influx in the lungs.[A39177]\r\n\r\n* Orthostatic hypotension - ibuprofen can induce sodium retention and antagonize the effect of diuretics which has been reported to be beneficial for patients with severe orthostatic hypotension.[A1651]\r\n\r\n* Dental pain - ibuprofen is used to manage acute and chronic orofacial pain.[A10901]\r\n\r\n* Minor pain - ibuprofen is widely used to reduce minor aches and pains as well as to reduce fever and manage dysmenorrhea. It is very commonly used for the relief of acute indications such as fever and tension headaches.[A39092]\r\n\r\n* Investigational uses - efforts have been put into developing ibuprofen for the prophylaxis of Alzheimer's disease, Parkinson disease, and breast cancer.[A39092]","pharmacodynamics":"Ibuprofen has multiple actions in different inflammatory pathways involved in acute and chronic inflammation. The main effects reported in ibuprofen are related to the control of pain, fever and acute inflammation by the inhibition of the synthesis of prostanoids by COX-1 and COX-2. Pain relief is attributed to peripheral affected regions and central nervous system effects in the pain transmission mediated by the dorsal horn and higher spinothalamic tract. Some reports have tried to link the pain regulation with a possible enhancement on the synthesis of endogenous cannabinoids and action on the NMDA receptors. The effect on pain has been shown to be related to the cortically evoked potentials.[A39190]\r\n\r\nThe antipyretic effect is reported to be linked to the effect on the prostanoid synthesis due to the fact that the prostanoids are the main signaling mediator of pyresis in the hypothalamic-preoptic region.[A39190]\r\n\r\nThe use of ibuprofen in dental procedures is attributed to the local inhibition of prostanoid production as well as to anti-oedemic activity and an increase of plasma beta-endorphins. Some reports have suggested a rapid local reduction of the expression of COX-2 in dental pulp derived by the administration of ibuprofen.[A39190]\r\n\r\nThe administration of ibuprofen in patients with rheumatic diseases has shown to control joint symptoms.[A39092] \r\n\r\nIbuprofen is largely used in OTC products such as an agent for the management of dysmenorrhea which has been proven to reduce the amount of menstrual prostanoids and to produce a reduction in the uterine hypercontractility.[A39181] As well, it has been reported to reduce significantly the fever and the pain caused by migraines.[A39182, A39183] This effect is thought to be related to the effect on platelet activation and thromboxane A2 production which produces local vascular effects in the affected regions. This effect is viable as ibuprofen can enter in the central nervous system.[A39190]\r\n\r\nIn the investigational uses of ibuprofen, it has been reported to reduce neurodegeneration when given in low doses over a long time.[A39184] On the other hand, its use in Parkinson disease is related to the importance of inflammation and oxidative stress in the pathology of this condition.[A39185] The use of ibuprofen for breast cancer is related to a study that shows a decrease of 50% in the rate of breast cancer.[A39186]","mechanism_of_action":"The exact mechanism of action of ibuprofen is unknown. However, ibuprofen is considered an NSAID and thus it is a non-selective inhibitor of cyclooxygenase, which is an enzyme involved in prostaglandin (mediators of pain and fever) and thromboxane (stimulators of blood clotting) synthesis via the arachidonic acid pathway.[L4614]\r\n\r\nIbuprofen is a non-selective COX inhibitor and hence, it inhibits the activity of both COX-1 and COX-2. The inhibition of COX-2 activity decreases the synthesis of prostaglandins involved in mediating inflammation, pain, fever, and swelling while the inhibition of COX-1 is thought to cause some of the side effects of ibuprofen including GI ulceration.[A39195]","toxicity":"The symptoms of overdose are presented in individuals that consumed more than 99 mg/kg. Most common symptoms of overdose are abdominal pain, nausea, vomiting, lethargy, vertigo, drowsiness (somnolence), dizziness and insomnia. Other symptoms of overdose include headache, loss of consciousness, tinnitus, CNS depression, convulsions and seizures. May rarely cause metabolic acidosis, abnormal hepatic function, hyperkalemia, renal failure, dyspnea, respiratory depression, coma, acute renal failure, and apnea (primarily in very young pediatric patients).[A39200]\r\n\r\nThe reported LD50 of ibuprofen is of 636 mg/kg in rat, 740 mg/kg in mouse and 495 mg/kg in guinea pig.[MSDS]","metabolism":"Ibuprofen is rapidly metabolized and biotransformed in the liver to the formation of major metabolites which are the hydroxylated and carboxylated derivatives.[A39092] As soon as it is absorbed, the R-enantiomer undergoes extensive enantiomeric conversion (53-65%) to the more active S-enantiomer _in vivo_ by the activity of alpha-methylacyl-CoA racemase.[A39194] \r\n\r\nIbuprofen metabolism can be divided in phase I which is represented by the hydroxylation of the isobutyl chains for the formation of 2 or 3-hydroxy derivatives followed by oxidation to 2-carboxy-ibuprofen and p-carboxy-2-propionate. These oxidative reactions are performed by the activity of the cytochrome P450 isoforms CYP 2C9, CYP 2C19 and CYP 2C8. Therefore, these enzymes participate in the oxidation of the alkyl side chain to hydroxyl and carboxyl derivatives. From this enzymes, the major catalyst in the formation of oxidative metabolites is the isoform CYP 2C9.[A39190]\r\n\r\nThe metabolic phase I is followed by a phase II in which the oxidative metabolites may be conjugated to glucuronide prior to excretion. This activity forms phenolic and acyl glucuronides.[A39190]","absorption":"It is very well absorbed orally and the peak serum concentration can be attained in 1 to 2 hours after extravascular administration. When ibuprofen is administered immediately after a meal there is a slight reduction in the absorption rate but there is no change in the extent of the absorption.[A39092] \r\n\r\nWhen orally administered, the absorption of ibuprofen in adults is very rapidly done in the upper GI tract.[A39190] The average Cmax, Tmax and AUC ranges around 20 mcg/ml, 2 h and 70 mcg.h/ml. These parameters can vary depending on the enantiomer form, route, and dose of administration.[A39190]","half_life":"The serum half-life of ibuprofen is 1.2-2 hours.[A39092] In patients with a compromised liver function, the half-life can be prolonged to 3.1-3.4 hours.[A39190]","protein_binding":"Ibuprofen dosage is more than 99% bound to plasma proteins and site II of purified albumin, binding appears to be saturable and becomes non-linear at concentrations exceeding 20 mcg/ml.[A39092]","route_of_elimination":"Ibuprofen is rapidly metabolized and eliminated in the urine thus, this via accounts for more than 90% of the administered dose. It is completely eliminated in 24 hours after the last dose and almost all the administered dose goes through metabolism, representing about 99% of the eliminated dose.[A39092] The biliary excretion of unchanged drug and active phase II metabolites represents 1% of the administered dose.[A39190]\r\n\r\nIn summary, ibuprofen is excreted as metabolites or their conjugates. The elimination of ibuprofen is not impaired by old age or the presence of renal impairment.[A39092]","volume_of_distribution":"The apparent volume of distribution of ibuprofen is of 0.1 L/kg.[A39195]","clearance":"The clearance rate ranges between 3-13 L/h depending on the route of administration, enantiomer type and dosage.[A39190]"}
{"drugbank_id":"DB01234","indication":"Dexamethasone and [ciprofloxacin] otic suspension is indicated for bacterial infections with inflammation in acute otitis media and acute otitis externa.[L10698] Intramuscular and intravenous injections are indicated for a number of endocrine, rheumatic, collagen, dermatologic, allergic, ophthalmic, gastrointestinal, respiratory, hematologic, neoplastic, edematous, and other conditions.[L10701] Oral tablets are indicated for the treatment of multiple myeloma.[L10710] An intravitreal implant is indicated for some forms of macular edema and non-infectious posterior uveitis affecting the posterior of the eye.[L10719] Various ophthalmic formulations are indicated for inflammatory conditions of the eye.[L10704,L10707,L10713,L10716,L10722,L10725]","pharmacodynamics":"Corticosteroids bind to the glucocorticoid receptor, inhibiting pro-inflammatory signals, and promoting anti-inflammatory signals.[A187463] Dexamethasone's duration of action varies depending on the route.[L10698,L10701,L10704,L10707,L10710,L10713,L10716,L10719,L10722,L10725] Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces.[A187463] Patients taking corticosteroids should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections.[A187463]","mechanism_of_action":"The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation.[A187463] Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days.[A187463]\r\n\r\nGlucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10.[A187463]\r\n\r\nLower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive.[A187463] High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels.[A187463]","toxicity":"The oral LD<sub>50<\/sub> in female mice was 6.5g/kg and 794mg/kg via the intravenous route.[L10701]\r\n\r\nOverdoses are not expected with otic formulations.[L10698] Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency.[A188405] Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment.[A188405]","metabolism":"Dexamethasone is 6-hydroxylated by CYP3A4 to 6\u001a- and 6\u001a-hydroxydexamethasone.[A187268] Dexamethasone is reversibly metabolized to 11-dehydrodexamethasone by corticosteroid 11-beta-dehydrogenase isozyme 2 and can also be converted back to dexamethasone by Corticosteroid 11-beta-dehydrogenase isozyme 1.[A10059,A188556]","absorption":"Absorption via the intramuscular route is slower than via the intravenous route.[L10701] A 3mg intramuscular dose reaches a C<sub>max<\/sub> of 34.6\u001a6.0ng/mL with a T<sub>max<\/sub> of 2.0\u001a1.2h and an AUC of 113\u001a38ng\\*h/mL.[A188718] A 1.5mg oral dose reaches a C<sub>max<\/sub> of 13.9\u001a6.8ng/mL with a T<sub>max<\/sub> of 2.0\u001a0.5h and an AUC of 331\u001a50ng\\*h/mL.[A188718] Oral dexamethasone is approximately 70-78% bioavailable in healthy subjects.[A188721]","half_life":"The mean terminal half life of a 20mg oral tablet is 4 hours.[L10710] A 1.5mg oral dose of dexamethasone has a half life of 6.6\u001a4.3h, while a 3mg intramuscular dose has a half life of 4.2\u001a1.2h.[A188718]","protein_binding":"Dexamethasone is approximately 77% protein bound in plasma.[L10710] The majority of protein binding is with serum albumin.[A188559] Dexamethasone does not significantly bind to corticosteroid binding protein.[A188559]","route_of_elimination":"Corticosteroids are generally eliminated predominantly in the urine.[A187436] However, dexamethasone is <10% elminated in urine.[L10710]","volume_of_distribution":"A 1.5mg oral dose of dexamethasone has a volume of distribution of 51.0L, while a 3mg intramuscular dose has a volume of distribution of 96.0L.[A188718]","clearance":"A 20mg oral tablet has a clearance of 15.7L/h.[L10710] A 1.5mg oral dose of dexamethasone has a clearance of 15.6\u001a4.9L/h while a 3.0mg intramuscular dose has a clearance of 9.9\u001a1.4L/h.[A188718]"}
{"drugbank_id":"DB01264","indication":"Darunavir, co-administered with ritonavir, and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) in children age 3 or above and adults with HIV-1 infection.[L9227]","pharmacodynamics":"Darunavir is an inhibitor of the human immunodeficiency virus (HIV) protease, which prevents HIV viral replication.[L9227] When administered with ritonavir in combination antiretroviral therapy, darunavir significantly decreases viral load and increases CD4 cell counts, decreasing the morbidity and mortality of HIV infection.[A2278,A2281,A191520]","mechanism_of_action":"The HIV-1 protease enzyme is necessary for viral precursor protein processing and viral maturation in preparation for infection, and is therefore a target for antiretroviral therapy for HIV.  Protease inhibitors are used as a part of highly active antiretroviral therapy (HAART) in patients diagnosed with HIV infection. It has been shown to effectively suppress the virus, leading to significantly decreased morbidity and mortality rates.[A2281]\r\n\r\nDarunavir, a HIV protease inhibitor, prevents HIV replication through binding to the enzyme, stopping the dimerization and the catalytic activity of HIV-1 protease. In particular, it inhibits the cleavage of HIV encoded Gag-Pol proteins[A191556] in cells that have been infected with the virus, halting the formation of mature virus particles, which spread the infection. The close contact that darunavir makes with the primary chains of the active site amino acids (Asp-29 and Asp-30) on the protease likely contributes to its potency and efficacy against resistant variants of HIV-1.[A2281] \r\n\r\nDarunavir is known to bind to different sites on the enzyme: the active site cavity and the surface of one of the flexible flaps in the protease dimer. Darunavir can adapt to changes in the shape of a protease enzyme due to its molecular flexibility.[A2281,A191526]","toxicity":"LD50 information for darunavir is not readily available in the literature.[A191562]  One-time doses of up to 3,200 mg of darunavir in an oral solution and up to 1,600 mg of the tablet formulation of darunavir with ritonavir have been given volunteers without significant symptoms.[L11988]\r\n\r\nInformation about an overdose with darunavir with ritonavir is limited. No specific antidote exists for this drug. Treatment of In the case of an overdose, employ general supportive measures. Monitor vital signs and clinical status. It is unlikely that darunavir not amenable to removal by dialysis due to its high level of protein binding.[L9227]","metabolism":"Darunavir is heavily oxidized and metabolized by hepatic cytochrome enzymes, mainly CYP3A.[L9227] Darunavir is extensively metabolized in subjects who do not receive a booster, primarily via carbamate hydrolysis, isobutyl aliphatic hydroxylation, and aniline aromatic hydroxylation, as well as both benzylic aromatic hydroxylation and glucuronidation.[A191502]","absorption":"The absolute oral bioavailability of one single 600 mg dose of darunavir alone and with 100 mg of ritonavir twice a day was 37% and 82%, respectively.[T762] Exposure to darunavir in boosted patients has been found to be 11 times higher than in unboosted patients.[A191502] Tmax is achieved approximately 2.4 to 4 hours after oral administration.[T762,L9227]\r\n\r\nWhen darunavir is taken with food, the Cmax and AUC of darunavir given with ritonavir increase by 30% when compared to the fasted state.[T762]\r\n\r\n","half_life":"The terminal elimination half-life of darunavir is approximately 15 hours when it is combined with ritonavir.[A2277,L9227]","protein_binding":"Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).[A191502,T762,L9227]","route_of_elimination":"A mass balance study in healthy volunteers demonstrated that after single dose administration of 400 mg 14C-darunavir, given with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of radiolabeled darunavir was obtained in the feces and urine, respectively.  Excretion of unchanged drug accounted for 8.0% of the darunavir dose in volunteers who were unboosted.[A191502]\r\n\r\nIn boosted darunavir administration, unchanged darunavir made up 48.8% of the excreted dose in boosted subjects due to inhibition of darunavir metabolism by ritonavir. Unchanged drug in the urine made up 1.2% of the administered dose in volunteers who where unboosted, and 7.7% in boosted volunteers.[A191502]\r\n\r\n","volume_of_distribution":"The volume of distribution of darunavir in one pharmacokinetic study in conjunction with ritonavir was 206.5 L (with a range of 161.0\u001a264.9) in healthy young adult volunteers.[A191544] Another pharmacokinetic study revealed a volume of distribution of 220 L.[A191553]","clearance":"Darunavir has a low renal clearance.[A191502] After intravenous administration, the clearance darunavir administered alone and  with 100 mg ritonavir twice daily, was 32.8 L/h and 5.9 L/h, respectively.[L9227]"}
{"drugbank_id":"DB01394","indication":"Colchicine is indicated for the prophylaxis and treatment of gout flares.  It is also indicated in Familial Mediterranean fever (FMF) in children and adults of 4 years of age and older. It is important to note that this medication is not a pain reliever to be used for other painful conditions. Consider analgesics for this purpose.[L8138] Some off-label uses of colchicine include the treatment of the manifestations of Behcet's syndrome, pericarditis, and postpericardiotomy syndrome.[A183932,A183935]","pharmacodynamics":"Colchicine reduces the pain resulting from gout and reduces flares of Familial Mediterranean fever by interfering with inflammatory pathways.[A183602,L8138] This drug has a narrow therapeutic index.[A184361]","mechanism_of_action":"The exact mechanism of action of colchicine has not been fully established, however likely occurs via the downstream inhibition of inflammation caused by tubulin disruption.[A183602] Studies have implied that that colchicine causes disruption of the inflammasome complex that is present in both monocytes and neutrophils, which normally leads to the activation of interleukin-1, an important mediator of inflammation.[A183605] In addition to the above actions, colchicine acts to interfere with pathways including neutrophil adhesion and recruitment, superoxide production, the RhoA/Rho effector kinase (ROCK) pathway, as well as a type of nuclear factor \u001a\u001a (NF-\u001a\u001a) pathway, reducing inflammation.[A183611] \r\n\r\nOn a molecular level, colchicine can be described as an anti-mitotic drug, blocking the mitotic activity cells in the metaphase part of the cell cycle. Specifically, colchicine binds to tubulin, forming complexes that bind to microtubules. This stops their elongation. At low concentrations, colchicine stops microtubule growth and, at elevated concentrations, colchicine causes the depolymerization of microtubules.[A183602]","toxicity":"The oral LD50 of colchicine in mice is 5.87 mg/kg.[L8189]\r\n\r\nOverdose information\r\n\r\nFatal overdoses have been reported in adults and children following the ingestion of colchicine. There are several stages involved in colchicine toxicity. The signs and symptoms generally occur within 24 hours of colchicine ingestion. Gastrointestinal disturbance, including abdominal pain, nausea, vomiting, diarrhea, and volume depletion. Elevated leucocyctes may also be detected during laboratory testing. Dangerous complications may occur during the second stage of a colchicine overdose, is generally during the time frame of 24 to 72 hours after ingestion. Multiorgan failure  may occur and death is usually caused by respiratory depression in addition to cardiovascular collapse.[A11504,L8138]\r\n\r\n\r\nIn the case of a colchicine overdose, gastric lavage and supportive measures to prevent shock should be undertaken. Treat symptoms related to the overdose. There is currently no antidote to a colchicine overdose. This drug should be kept out of the reach of children. Colchicine is not well removed by dialysis.[L8138]","metabolism":"Colchicine is found to be metabolized in the liver and demethylated to major metabolites, which include 2-O-demethylcolchicine and 3-O-demethylcolchicine, and one minor metabolite, 10-O-demethylcolchicine (colchiceine). According to in vitro studies, CYP3A4 metabolizes colchicine to 2- and 3-demethylcolchicine.[L8138,L8192]","absorption":"Colchicine is rapidly absorbed after oral administration from the gastrointestinal tract. During a pharmacokinetic study, a mean Cmax of 2.5 ng/mL was achieved within 1-2 h (range 0.5 to three hours) after an orally administered dose of colchicine. The bioavailability of colchicine is about 45%, according to the FDA label, however, another reference indicates that the bioavailability is highly variable, ranging from 24 to 88%.[A183608]  In a multiple-dose study of colchicine administration at a dose of 1 mg per day, steady-state concentrations were achieved by 8 days following administration.[A183608]","half_life":"After several doses of 0.6 mg twice daily, the average elimination half-life of colchicine ranges from 26.6 to 31.2 hours.[L8138] Another reference measures that the elimination half-life ranges from 20 to 40 hours.[A183608]","protein_binding":"The plasma protein binding for colchicine is low to moderate, at 39 \u001a 5%, and it is mainly bound to albumin.[A183608,L8138]","route_of_elimination":"In a pharmacokinetic study of healthy research subjects(n=12), 40% to 65% of a 1 mg oral colchicine dose was measured as unchanged drug in the urine. Both enterohepatic recirculation and biliary excretion are routes which are involved with the excretion of colchicine.[A11504,L8138]","volume_of_distribution":"According to the FDA label, the mean apparent volume of distribution in young and healthy patients is calculated to be about 5-8 L/kg. It is known to cross the placenta and to distribute into the breast milk.[L8138] Colchicine has been found to distribute to various tissues but mainly into the bile, liver, and kidney tissues. Smaller amounts have been detected in the heart, lungs, intestinal tissue, and stomach.[L8192]","clearance":"The FDA label reports a clearance of and 0.0292 \u001a 0.0071 to 0.0321 \u001a 0.0091 mL/min after a single oral dose of one 0.6 mg of colchicine. Patients with end-stage renal impairment showed a 75% lower clearance of colchicine.[L8138] In a pharmacokinetic study of patients with Familial Mediterranean Fever (FMF), the apparent mean clearance was calculated at  0.726 \u001a 0.110 L/h/kg.[A183953]"}
{"drugbank_id":"DB01601","indication":"The combination product lopinavir/ritonavir, marketed under the brand name Kaletra, is indicated in combination with other antiretrovirals for the treatment of HIV-1 infection in adults and pediatric patients \u001a14 days old.[L11163]","pharmacodynamics":"Lopinavir inhibits the activity of an enzyme critical for the HIV viral lifecycle.[L11163] It has a moderate duration of action necessitating once or twice daily dosing.[L11163] Lopinavir, like other protease inhibitors, has a propensity for participating in drug interactions - use caution when administering lopinavir to patients maintained on other pharmaceutical agents as pharmacodynamic and pharmacokinetic interactions are common. Fatal hepatotoxicity and pancreatitis have been noted in patients undergoing therapy with lopinavir and patients with an increased baseline risk of these events should be monitored closely throughout therapy.[L11163]","mechanism_of_action":"The HIV lifecycle is comprised of 3 distinct stages: assembly, involving creation and packaging of essential viral components; budding, wherein the viral particle crosses the host cell plasma membrane and forms a lipid envelope; and maturation, wherein the viral particle alters its structure and becomes infectious.[A191712] At the center of this lifecycle is the Gag polyprotein which, along with the products of its proteolysis, coordinate these stages and function as the major structural proteins of the virus. The HIV-1 protease enzyme, a dimeric aspartic protease, is the enzyme responsible for cleaving the Gag polyprotein and thus plays a critical role in many aspects of the HIV viral lifecycle.[A191712]\r\n\r\nLopinavir is an inhibitor of the HIV-1 protease enzyme.[L11163] Its design is based on the \"peptidomimetic\" principle, wherein the molecule contains a hydroxyethylene scaffold which mimics the normal peptide linkage (cleaved by HIV protease) but which itself cannot be cleaved.[A191757] By preventing HIV-1 protease activity, and thus the proteolysis of the Gag polyprotein, lopinavir results in the production of immature, non-infectious viral particles.","toxicity":"As lopinavir is only available in combination with ritonavir, experience with acute lopinavir overdose in isolation is limited. The risk related to overdose appears more pronounced in pediatric patients. One case report detailed a fatal cardiogenic shock in a 2.1kg infant following an approximately 10-fold overdose of Kaletra oral solution, while other reported reactions to overdose in infants include complete AV block, cardiomyopathy, lactic acidosis, and acute renal failure. The oral Kaletra solution is highly concentrated, posing a greater risk of overdose, and contains approximately 42% (v/v) ethanol, further increasing risk in children and infants.[L11163]\r\n\r\nThere is no antidote for lopinavir overdose. Treatment of overdose should consist largely of supportive measures and close observation of vital signs and clinical status of the affected patient. Consideration should be given to the removal of unabsorbed drug using gastric lavage or activated charcoal, if clinically indicated. Dialysis is unlikely to be of benefit as lopinavir is highly protein-bound, but may help to remove ethanol and propylene glycol from the circulation in the case of overdose with Kaletra oral solution.[L11163]","metabolism":"Lopinavir undergoes extensive oxidative metabolism, almost exclusively via hepatic CYP3A isozymes.[L12063] Co-administration with ritonavir, a potent inhibitor of CYP3A enzymes, helps to stave off lopinavir's biotransformation and increase plasma levels of active antiviral drug. Twelve metabolites have been identified _in vitro_, with the C-4 oxidation products M1, M3, and M4 being the predominant metabolites found in plasma.[A191919] The structures of these primary metabolites have been identified, but precise structural information regarding the remaining minor metabolites has not been elucidated.","absorption":"When administered alone, lopinavir has exceptionally low oral bioavailability (~25%) - for this reason, it is exclusively co-administered with ritonavir, which dramatically improves bioavailability, hinders drug metabolism, and allows for the attainment of therapeutic lopinavir concentrations.[A191715,A191748] Following oral administration of lopinavir/ritonavir, maximal plasma concentrations are achieved at approximately 4.4 hours (T<sub>max<\/sub>), and the C<sub>max<\/sub> and AUC<sub>tau<\/sub> are 9.8 \u001a 3.7 - 11.8 \u001a 3.7 \u001ag/mL and 92.6 \u001a 36.7 - 154.1 \u001a 61.4 \u001ag\u001ah/mL, respectively.[L11163]\r\n\r\nRelative to administration in the fasted state, administration with a meal increases the AUC of the tablet formulation slightly (~19%) but dramatically increases the AUC of the oral solution formulation (~130%).[L11163]","half_life":"The elimination half-life of lopinavir is 6.9 \u001a 2.2 hours.[L11163]","protein_binding":"Lopinavir is >98% protein-bound in plasma.[L11163] It binds to both alpha-1-acid glycoprotein and albumin, but exhibits a greater affinity for alpha-1-acid glycoprotein.[L12063]","route_of_elimination":"Lopinavir is primarily eliminated in the feces. Following oral administration, approximately 10.4 \u001a 2.3% of the administered dose is excreted in the urine and 82.6 \u001a 2.5% is excreted in the feces.[L11163] Unchanged parent drug accounted for 2.2% and 19.8% of the administered dose in urine and feces, respectively.[L12063]","volume_of_distribution":"The volume of distribution of lopinavir following oral administration is approximately 16.9 L.[L11163]","clearance":"The estimated apparent clearance following oral administration is approximately 6-7 L/h.[A191715,L12063]"}
{"drugbank_id":"DB05941","indication":"Leronlimab is currently being investigated for the treatment of a number of cancers[A192858] and HIV.[A3922]\r\n\r\nRecently leronlimab has begun a phase II clinical trial in severely ill COVID-19 patients.[L12684] Preliminary data shows a reduction in the 'cytokine storm', particularly IL-6, as well as a normalization of the CD4/CD8 T-cell ratio.[L12684] These results may mitigate immune mediate injury seen in severely ill COVID-19 patients.[L12684]","pharmacodynamics":"Leronlimab is a humanized monoclonal antibody that binds CCR5 being investigated for it's anti-HIV, immunomodulatory, and anti-cancer effects.[A3922,A192858,L12684]","mechanism_of_action":"CCR5 is a helical protein with multiple extracellular regions with adjacent G proteins.[A3922,A192858] When a chemokine binds CCR5, the G\u001a\u001a\u001a trimer phosphorylates GDP to GTP and G\u001a dissociates.[A192858] Activated G\u001a activates adenylate cyclase, and increasing levels of cyclic AMP activate cytosolic protein kinase A.[A192858] Further downstream effects of CCR5 signalling include activation of NF-\u001aB and IL-6, as well as effects on cell proliferation, migration, and survival.[A192858,L12684]\r\n\r\nHIV enters cells expressing CD4 and a fusion coreceptor such as CCR5 and CXCR4.[A3922] Leronlimab is a monoclonal antibody which binds to multiple extracellular regions of the CCR5 receptor, preventing the entry of HIV into the cell.[A3922]\r\n\r\nLeronlimab's blocking of CCR5 is being investigated in cancer treatment, for it's effect on the cell cycle and immuno-modulation.[A192858]\r\n\r\nLeronlimab is also being investigated as a treatment for patients severely ill with COVID-19 due to it's effects on mitigating the cytokine storm and preventing immune-mediated injury.[L12684]","toxicity":"Data regarding overdose of leronlimab is not readily available.","metabolism":"Data regarding the metabolism of leronlimab is not readily available. However, as a monoclonal antibody it is expected to be degraded to smaller proteins and amino acids by proteolytic enzymes.","absorption":"A 162mg subcutaneous dose reaches a C<sub>max<\/sub> of 6.1mg/L, with a T<sub>max<\/sub> of 32 hours, and an AUC of 24.4mg\\*day/L.[A192846] A 324mg subcutaneous dose reaches a C<sub>max<\/sub> of 13.8mg/L, with a T<sub>max<\/sub> of 56 hours, and an AUC of 58.8mg\\*day/L.[A192846]","half_life":"The half life of a 162mg subcutaneous dose is 3.4 days while the half life of a 324mg subcutaneous dose is 3.7 days.[A192846]","protein_binding":"Data regarding the protein binding of leronlimab is not readily available.","route_of_elimination":"Data regarding the route of elimination of leronlimab is not readily available.","volume_of_distribution":"Data regarding the volume of distribution of leronlimab is not readily available.","clearance":"Data regarding the clearance of leronlimab is not readily available."}
{"drugbank_id":"DB06273","indication":"Tocilizumab is indicated to treat moderate to severe rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome.[L12789]","pharmacodynamics":"Tocilizumab is an IL-6 inhibiting monoclonal antibody used to treat autoimmune and inflammatory conditions.[L12789] Tocilizumab has a long duration of action as it is generally given every 4 weeks and has a wide therapeutic index.[L12789] Patients should be counselled regarding the risk of infections, GI perforation, and hepatotoxicity.[L12789]","mechanism_of_action":"Interleukin 6 (IL-6) is a pro-inflammatory cytokine produced by cells including T-cells, B-cells, lymphocytes, monocytes, fibroblasts.[L12789] IL-6 rapidly induces C-reactive protein, serum amyloid A, fibrinogen, haptoglobin, and \u001a-1-antichymotrypsin while inhibiting production of fibronectin, albumin, and transferrin.[A193287] IL-6 also induces antibody production, induces cytotoxic T-cell differentiation, and inhibits regulatory T-cell differentiation.[A193287] Tocilizumab binds soluble and membrane bound IL-6 receptors, preventing IL-6 mediated inflammation.[L12789]","toxicity":"Data regarding overdoses of tocilizumab are not readily available.[L12789] Patients experiencing an overdose may develop neutropenia.[L12789] In case of overdose, monitor patients for signs of adverse reactions and provide symptomatic and supportive treatment.[L12789]","metabolism":"Tocilizumab, like other monoclonal antibodies, is expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes.[A19126]","absorption":"A 162mg subcutaneous dose given weekly has a C<sub>max<\/sub> of 51.3\u001a23.2\u001ag/mL and an AUC of 8254\u001a3833\u001ag\\*h/mL.[A193293] A 162mg subcutaneous dose given every 2 weeks has a C<sub>max<\/sub> of 13\u001a8.3\u001ag/mL and an AUC of 3460\u001a2530\u001ag\\*h/mL.[A193293] A 162mg subcutaneous dose given every 4 weeks has a C<sub>max<\/sub> of 154\u001a42\u001ag/mL and an AUC of 39216\u001a14304\u001ag\\*h/mL.[A193293]","half_life":"The half life of tocilizumab is concentration dependent.[L12789] The terminal half life in rheumatoid arthritis patients is 21.5 days.[L12789] The absorption half life in rheumatoid arthritis and giant cell arteritis patients was 4 days, and in polyarticular juvenile idiopathic arthritis patients and systemic juvenile idiopathic arthritis patients was 2 days.[L12789]","protein_binding":"Data regarding the serum protein binding of tocilizumab is not readily available.[L12789]","route_of_elimination":"Data regarding the exact route of elimination of monoclonal antibodies is not readily available.[A19126,L12789]","volume_of_distribution":"In rheumatoid arthritis patients, the central volume of distribution is 3.5L, the peripheral volume of distribution is 2.9L, and the volume of distribution at steady state is 6.4L.[L12789] In giant cell arteritis patients, the central volume of distribution is 4.09L, the peripheral volume of distribution if 3.37L, and the volume of distribution at steady state is 7.46L.[L12789] In pediatric patients with polyarticular juvenile arthritis, the central volume of distribution is 1.98L, the peripheral volume of distribution is 2.1L, and the volume of distribution at steady state is 4.08L.[L12789] In pediatric patients with systemic juvenile idiopathic arthritis, the central volume of distribution is 1.87L, the peripheral volume of distribution is 2.14L, and the volume of distribution at steady state is 4.01L.[L12789]","clearance":"The linear clearance in rheumatoid arthritis patients is 12.5mL/h, in giant cell arteritis patients is 6.7mL/h, in polyarticular juvenile idiopathic arthritis patients is 5.8mL/h, and in systemic juvenile idiopathic arthritis is 5.7mL/h.[L12789] Clearance is dose dependent and changes from non linear at low doses to linear at higher doses.[L12789]"}
{"drugbank_id":"DB08868","indication":"Fingolimod is indicated for the treatment of patients aged 10 and above with relapsing forms of multiple sclerosis, which may include clinically isolated syndrome, relapsing-remitting disease, as well as active secondary progressive disease.[L12651]\r\n\r\nThis drug is being studied for administration in patients infected with COVID-19 with a high risk for acute respiratory distress syndrome, or ARDS.[L12654] As of April 3 2020, this is currently not an approved indication and clinical trials are underway.[L12657]","pharmacodynamics":"In multiple sclerosis, fingolimod binds to sphingosine receptors, reducing its associated neuroinflammation.[L12651]In COVID-19, it may reduce lung inflammation and improve the clinical outcomes of patients with this disease.[L12654] \r\n\r\nCardiovascular effects\r\n\r\nFingolimod causes a transient reduction in heart rate and AV conduction during treatment initiation. It has the potential to prolong the QT interval.[L12654]\r\n\r\n\r\n","mechanism_of_action":"Sphingosine\u001a1\u001aphosphate (S1P) is an important phospholipid that binds to various G\u001aprotein\u001acoupled receptor subtypes, which can be identified as S1P1\u001a5R. S1P and the receptors it binds to perform regular functions in the immune, cardiovascular, pulmonary, and nervous system.[A189321,A192744] S1P can be expressed ubiquitously, playing an important role in regulating inflammation.  S1P1R, S1P2R, and S1P3R receptors can be found in the cardiovascular, immune, and central nervous systems. S1P4R is found on lymphocytic and hematopoietic cells, while S1P5R expression is found only on the spleen (on natural killer cells) or in the central nervous system.[A189333]\r\n\r\nThe active form of the drug, fingolimod phosphate,  is a sphingosine 1-phosphate receptor modulator that exerts its mechanism of action in MS by binding to various sphingosine 1-phosphate receptors (1, 3, 4, and 5). It suppresses the exit of lymphocytes from lymph nodes, leading to a lower level of lymphocytes circulating in peripheral circulation. This reduces the inflammation that is associated with MS. The mechanism of action of fingolimod is not fully understood,  but may be related to reduced lymphocyte circulation into the central nervous system.[A176474,L12651]\r\n\r\nImmune modulating treatment such as fingolimod is not typically employed for SARS-CoV-2 pneumonia. Despite this, with the tissue findings of pulmonary edema and hyaline membrane formation, the timely use of immune modulators such as fingolimod can be considered to prevent acute respiratory distress syndrome (ARDS) associated with COVID-19. [L12654]\r\n","toxicity":"The LD50 of fingolimod in rats ranges from 300-600 mg/kg.[A192906]\r\n\r\nPrescribing information for fingolimod does not mention symptoms or management of an overdose [L12651], however, a case report of an intentional overdose with 14mg of fingolimod and 2g phenoxymethylpenicillin resulted in hypotension in bradycardia, resolved by administering atropine.[A192909] Since fingolimod has been associated with cardiotoxicity, it would be reasonable to expect cardiac effects such as bradycardia and heart block in the case of an overdose.[A192912,L12651]","metabolism":"Sphingosine kinase metabolizes fingolimod to an active metabolite, fingolimod phosphate. Fingolimod metabolism occurs via 3 major metabolic pathways: firstly, phosphorylation of the (S)-enantiomer of fingolimod-phosphate (pharmacologically active), secondly, oxidation by cytochrome P450 4F2 (CYP4F2), and thirdly, fatty acid-like metabolism to various inactive metabolites. The formation of inactive non-polar ceramide analogs of fingolimod also occurs during its metabolism.[A38022,L12651]","absorption":"Fingolimod is slowly but efficiently absorbed in the gastrointestinal tract. AUC varies greatly, depending on the patient, and pharmacokinetic studies demonstrate a range of AUC values for fingolimod.[A38022] The Tmax of fingolimod ranges between 12-16 hours and its bioavailability is 90-93%. Steady-state concentrations of fingolimod are achieved within 1-2 months after initiation when it is administered in a single daily dose.[A38022,L12651]","half_life":"The half-life of fingolimod and its active metabolite ranges from 6-9 days.[A38022,L12651]","protein_binding":"The protein binding of fingolimod and its active metabolite exceeds 99.7%.[A38022,L12651]","route_of_elimination":"About 81% of an oral dose of fingolimod is excreted in the urine in the form of inactive metabolites. Intact fingolimod and its active metabolite account for less than 2.5% of the dose, and can be found excreted in the feces.[L12651]","volume_of_distribution":"The volume of distribution of fingolimod is about 1200\u001a260 L. It is approximately 86% distributed in the red blood cells (RBC).[A38022,L12651]","clearance":"Fingolimod blood clearance is 6.3\u001a2.3 L/h[L12651], according to prescribing information. Another resource mentions it ranges from 6-8 L/h.[A38022]"}
{"drugbank_id":"DB11574","indication":"Elbasvir, when used in combination with [grazoprevir] as the combination product Zepatier, is indicated for use with or without [ribavirin] for the treatment of chronic HCV genotypes 1 or 4 infection in adults.[L10253]","pharmacodynamics":"Elbasvir is classified as a direct-acting antiviral (DAA) and prevents viral replication in HCV genotypes 1a, 1b, and 4.[L10253]","mechanism_of_action":"Elbasvir is an inhibitor of the HCV non-structural protein 5A. While the precise role of this protein is unknown, it is essential to viral replication and virion assembly.[synthesis] Potential modes of action of NS5A inhibitors like elbasvir include blocking signaling interactions, redistribution of NS5A from the endoplasmic reticulum to the surface of lipid droplets, and modification of the HCV replication complex.[A19593]\r\n\r\nComputational target-based _in silico_ research suggests that elbasvir may carry activity at several proteins required for replication of SARS-CoV-2 - namely RNA-dependent RNA polymerase, helicase, and papain-like proteinase - although specific activity has yet to be affirmed by follow-up clinical studies.[A193257]","toxicity":"The most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache, and nausea.[L10253]","metabolism":"Elbasvir is partially eliminated by oxidative metabolism meditated by CYP3A.[L10253] No circulating metabolites of elbasvir have been detected in human plasma.","absorption":"Elbasvir reaches peak plasma concentration 3-6 hours after administration[L10253] and has an absolute bioavailability of 32%. When co-administered with food, the peak concentration of elbasvir increases 1.5-fold, but this increase in exposure is not likely to be clinically relevant.","half_life":"The geometric mean apparent terminal half-life for elbasvir is 24 hours in HCV-infected subjects.[L10253]","protein_binding":"Elbasvir is more than 99.9% bound to plasma proteins.[L10253] It binds both human serum albumin and \u001a1-acid glycoprotein.","route_of_elimination":"Elbasvir is mainly eliminated in the feces (90%) with very little eliminated in the urine (<1%).[L10253]","volume_of_distribution":"Elbasvir has an estimated apparent volume of distribution of 680 liters.[L10253] It is thought to distribute into most tissues including the liver.","clearance":"The clearance of elbasvir has not been determined.[L10253]"}
{"drugbank_id":"DB11676","pharmacodynamics":"Galidesivir is an adenosine analogue with a broad-spectrum antiviral activity against RNA viruses, including flaviviruses, togaviruses, bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses, filoviruses, orthomyxoviruses, and picornaviruses.[A191769]","mechanism_of_action":"Galidesivir works by binding to viral RNA polymerase where the natural nucleotide would bind, leading to the structural change in the viral enzyme due to altered electrostatic interactions. Disruption of viral RNA polymerase activity results in premature termination of the elongating RNA strand.[A191622,A191769]"}
{"drugbank_id":"DB12466","indication":"In 2014, favipiravir was approved in Japan to treat cases of influenza that were unresponsive to conventional treatment.[A191721] Given its efficacy at targetting several strains of influenza, it has been investigated in other countries to treat novel viruses including Ebola and most recently, COVID-19.[A191688,A191724,L12012]","pharmacodynamics":"Favipiravir functions as a prodrug and undergoes ribosylation and phosphorylation intracellularly to become the active favipiravir-RTP.[A191688,A191724] Favipiravir-RTP binds to and inhibits RNA dependent RNA polymerase (RdRp), which ultimately prevents viral transcription and replication.[A191688,A191691]","mechanism_of_action":"The mechanism of action of favipiravir is novel compared to existing influenza antivirals that primarily prevent entry and exit of the virus from cells.[A191688] The active favipiravir-RTP selectively inhibits RNA polymerase and prevents replication of the viral genome.[L12075] There are several hypotheses as to how favipiravir-RTP interacts with RNA dependent RNA polymerase (RdRp).[A191688] Some studies have shown that when favipiravir-RTP is incorporated into a nascent RNA strand, it prevents RNA strand elongation and viral proliferation.[A191688] Studies have also found that the presence of purine analogs can reduce favipiravir\u001as antiviral activity, suggesting competition between favipiravir-RTP and purine nucleosides for RdRp binding.[A191688]\r\n\r\nAlthough favipiravir was originally developed to treat influenza, the RdRp catalytic domain (favipiravir's primary target), is expected to be similar for other RNA viruses.[A191688] This conserved RdRp catalytic domain contributes to favipiravir's broad-spectrum coverage.[A191688]","toxicity":"Based on single-dose toxicity studies, the lethal dose for oral and intravenous favipiravir in mice is estimated to be >2000 mg/kg.[L12075] In rats, the lethal dose for oral administration is  >2000 mg/kg, while the lethal dose in dogs and monkeys is  >1000 mg/kg.[L12075] Symptoms of overdose appear to include but are not limited to reduced body weight, vomiting, and decreased locomotor activity.[L12075]\r\n\r\nIn repeat-dose toxicity studies involving dogs, rats, and monkeys, notable findings after administration of oral favipiravir included: adverse effects on hematopoietic tissues such as decreased red blood cell (RBC) production, and increases in liver function parameters such as aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and total bilirubin, and increased vacuolization in hepatocytes.[L12075] Testis toxicity was also noted.[L12075]\r\n\r\nFavipiravir is known to be teratogenic; therefore, administration of favipiravir should be avoided in women if pregnancy is confirmed or suspected.[A191688,A192066]\r\n\r\nToxicity information regarding favipiravir in humans is not readily available.","metabolism":"Favipiravir is extensively metabolized with metabolites excreted mainly in the urine.[A191724] The antiviral undergoes hydroxylation primarily by aldehyde oxidase and to a lesser extent by xanthine oxidase to the inactive metabolite, T705M1.[A191724]","absorption":"The bioavailability of favipiravir is almost complete at 97.6%.[L12075] The mean Cmax for the recommended dosing schedule of favipiravir is 51.5 ug/mL.[L12075]\r\n\r\nStudies comparing the pharmacokinetic effects of multiple doses of favipiravir in healthy American and Japanese subjects are below: \r\n\r\nJapanese subjects First Dose: \r\nCmax = 36.24 ug/mL\r\ntmax = 0.5 hr\r\nAUC = 91.40 ugxhr/mL\r\n\r\nAmerican subjects First Dose:\r\nCmax = 22.01 ug/mL\r\ntmax = 0.5 hr\r\nAUC = 44.11 ugxhr/mL\r\n\r\nJapanese Subjects Final Dose:\r\nCmax = 36.23 ug/mL\r\nTmax = 0.5 hr\r\nAUC = 215.05 ugxhr/mL\r\n\r\nAmerican Subjects Final Dose:\r\nCmax = 23.94 ug/mL\r\nTmax = 0.6 hr\r\nAUC = 73.27 ugxhr/mL\r\n\r\nWhen favipiravir was given as a single dose of 400 mg with food, the Cmax decreased.[L12075] It appears that when favipiravir is given at a higher dose or in multiple doses, irreversible inhibition of aldehyde oxidase (AO) occurs and the effect of food on the Cmax is lessened.[L12075]","half_life":"The elimination half-life of favipiravir is estimated to range from 2 to 5.5 hours.[A191721]","protein_binding":"Favipiravir is 54% plasma protein-bound.[A191721] Of this fraction, 65% is bound to serum albumin and 6.5% is bound to \u001a1-acid glycoprotein.[L12075]","route_of_elimination":"Favipiravir's metabolites are predominantly renally cleared.[A191721]","volume_of_distribution":"The apparent volume of distribution of favipiravir is 15 - 20 L.[A191727]","clearance":"The recommended oral dosing regimen for favipiravir is as follows: Day 1: 1600 mg twice daily; Days 2-5: 600 mg twice daily.[L12075] \r\n\r\nThe reported CL/F for favipiravir 1600 mg dosed once daily is 2.98 L/hr \u001a0.30 and the CL/F values for favipiravir 600 mg dosed twice daily on days 1-2 and once daily on days 3-7 were 6.72 L/hr \u001a1.68 on Day 1, and 2.89 L/hr \u001a0.91 on Day 7.[L12075] There is currently no reported clearance data for favipiravir 1600 mg dosed twice daily."}
{"drugbank_id":"DB12668","indication":"Metenkefalin is indicated in Bosnia for the treatment of relapsing-remitting multiple sclerosis.[L13889]","mechanism_of_action":"Metenkefalin is an agonist of \u001a and \u001a opioid receptors.[A203246] It also causes immunostimulation at low doses and immunosuppression at higher doses.[A203246] Metenkefalin can also inhibit the production of aldosterone, deoxycorticosterone, and corticosterone.[A203261] Unfortuneately, the mechanisms by which these effects occur have not been well described in the literature.","toxicity":"Data regarding overdoses of metenkefalin are not readily available.[L13889] Animal overdose studies have not determined an LD<sub>50<\/sub>.[L13889]","absorption":"Metenkefalin reaches a C<sub>max<\/sub> of 1266.14pg/mL, with a T<sub>max<\/sub> of 0.16h, and an AUC of 360.64pg\\*h/mL.[L13889]","half_life":"The half life of metenkefalin is 4.2-39 minutes.[L13889]"}
{"drugbank_id":"DB13609","indication":"Umifenovir is currently licensed in China and Russia for the prophylaxis and treatment of influenza and other respiratory viral infections.[A191475] It has demonstrated activity against a number of viruses and has been investigated in the treatment of _Flavivirus_,[A191388] Zika virus,[A191391] foot-and-mouth disease,[A191394] Lassa virus,[A191403] Ebola virus,[A191403] and herpes simplex.[A191409] In addition, it has shown _in vitro_ activity against hepatitis B and C viruses, chikungunya virus, reovirus, Hantaan virus, and coxsackie virus B5.[A191475,A191412]\r\n\r\nUmifenovir is currently being investigated as a potential treatment and prophylactic agent for the prevention of COVID-19 caused by SARS-CoV-2 infections.[A191385,A191550]","pharmacodynamics":"Umifenovir exerts its antiviral effects via both direct-acting virucidal activity and by inhibiting one (or several) stage(s) of the viral life cycle.[A191475] Its broad-spectrum of activity covers both enveloped and non-enveloped RNA and DNA viruses. It is relatively well-tolerated and possesses a large therapeutic window - weight-based doses up to 100-fold greater than those used in humans failed to produce any pathological changes in test animals.[A191475]\r\n\r\nUmifenovir does not appear to result in significant viral resistance. Instances of umifenovir-resistant influenza virus demonstrated a single mutation in the HA2 subunit of influenza hemagglutinin, suggesting resistance is conferred by prevention of umifenovir\u001as activity related to membrane fusion. The mechanism through which other viruses may become resistant to umifenovir requires further study.[A191475]","mechanism_of_action":"Umifenovir is considered both a direct-acting antiviral (DAA) due to direct virucidal effects and a host-targeting agent (HTA) due to effects on one or multiple stages of viral life cycle (e.g. attachment, internalization), and its broad-spectrum antiviral activity is thought to be due to this dual activity.[A191475] It is a hydrophobic molecule capable of forming aromatic stacking interactions with certain amino acid residues (e.g. tyrosine, tryptophan), which contributes to its ability to directly act against viruses. Antiviral activity may also be due to interactions with aromatic residues within the viral glycoproteins involved in fusion and cellular recognition,[A191397,A191406] with the plasma membrane to interfere with clathrin-mediated exocytosis and intracellular trafficking,[A191433] or directly with the viral lipid envelope itself (in enveloped viruses).[A191475,A191469] Interactions at the plasma membrane may also serve to stabilize it and prevent viral entry (e.g. stabilizing influenza hemagglutinin inhibits the fusion step necessary for viral entry).[A191475]\r\n\r\nDue to umifenovir\u001as ability to interact with both viral proteins and lipids, it may also interfere with later stages of the viral life cycle. Some virus families, such as _Flaviviridae_, replicate in a subcellular compartment called the membranous web - this web requires lipid-protein interactions that may be hindered by umifenovir. Similarly, viral assembly of hepatitis C viruses is contingent upon the assembly of lipoproteins, presenting another potential target.[A191475]","toxicity":"The oral LD<sub>50<\/sub> of umifenovir in mice and rats has been reported as 340-400 mg/kg and >3000 mg/kg, respectively.[A191475] Chronic administration of doses 10-50 times the therapeutic human dose resulted in no pathological changes to animal subjects.\r\n\r\nFurther information regarding the management of umifenovir overdose is unavailable.","metabolism":"Umifenovir is highly metabolized in the body, primarily in hepatic and intestinal microsomess, with approximately 33 metabolites having been observed in human plasma, urine, and feces.[A191499] The principal phase I metabolic pathways include sulfoxidation, N-demethylation, and hydroxylation, followed by phase II sulfate and glucuronide conjugation. In the urine, the major metabolites were sulfate and glucuronide conjugates, while the major species in the feces was unchanged parent drug (~40%) and the M10 metabolite (~3.0%). In the plasma, the principal metabolites are M6-1, M5, and M8 - of these, M6-1 appears of most importance given its high plasma exposure and long elimination half-life (~25h), making it a potentially important player in the safety and efficacy of umifenovir.[A191499]\r\n\r\nEnzymes involved in the metabolism of umifenovir include members of the cytochrome P450 family (primarily CYP3A4), flavin-containing monooxygenase (FMO) family, and UDP-glucuronosyltransferase (UGT) family (specifically UGT1A9 and UGT2B7).[A191499,A191454,A191424]","absorption":"Umifenovir is rapidly absorbed following oral administration, with an estimated T<sub>max<\/sub> between 0.65-1.8 hours.[A191499,A191508,A191475] The C<sub>max<\/sub> has been estimated as 415 - 467 ng/mL and appears to increase linearly with dose,[A191499,A191508] and the AUC<sub>0-inf<\/sub> following oral administration has been estimated to be approximately 2200 ng/mL/h.[A191499,A191508]","half_life":"The half-life of umifenovir following oral administration has been estimated to be between 17-21 hours.[A191475,A191499] Serum half-lives of the M5, M6-1, and M8 metabolites were found to be 26.3 \u001a 5.9, 25.0 \u001a 5.4, and 25.7 \u001a 8.8, respectively.[A191499]","protein_binding":"Data regarding protein-binding of umifenovir are currently unavailable.","route_of_elimination":"The major route of elimination is via the feces. Approximately 40% of an ingested dose is excreted unchanged, of which 38.9% is excreted in the bile and 0.12% excreted through the kidneys.[A191508] The total recovery of parent drug and metabolites in the urine accounts for less than 1% of an ingested dose.[A191499]","volume_of_distribution":"Data regarding the volume of distribution of umifenovir are currently unavailable.","clearance":"In a study involving healthy male Chinese volunteers, the oral clearance of umifenovir was found to be 99 \u001a 34 L/h.[A191499]"}
{"drugbank_id":"DB14761","indication":"Remdesivir has an FDA Emergency Use Authorization for use in adults and children with suspected or confirmed COVID-19  in hospital with an SpO2 \u001a94%.[L13239] This is not the same as an FDA approval.[L12609]\r\n\r\nThe FDA Emergency Use Authorization suggests a loading dose of 200mg once daily in patients \u001a 40 kg or 5 mg/kg once daily in patients 3.5 kg to less than 40 kg, followed by a maintenance dose of 100mg once daily in patients \u001a 40 kg or 2.5 mg/kg once daily in patients 3.5 kg to less than 40 kg.[L13239] Patients not needing invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) should be treated for 5 days (including the loading dose on day 1), up to 10 days if they do not show improvement.[L13239] Patients requiring invasive mechanical ventilation or ECMO should be treated for 10 days.[L13239]\r\n\r\nClinical trials used a regimen of 200mg once daily on the first day, followed by 100mg once daily for another 9 days.[A191931,L12174,L12177] Early data suggests that some patients may benefit from only 5 days of treatment.[A198810]\r\n\r\nRemdesivir was originally investigated as a treatment for Ebola virus, but has potential to treat a variety of RNA viruses.[A191379] Its activity against the coronavirus (CoV) family of viruses, such as SARS-CoV and MERS-CoV, was described in 2017,[A191382] and it is also being investigated as a potential treatment for SARS-CoV-2 infections.[A191427,A193254]","pharmacodynamics":"Remdesivir is a nucleoside analog used to inhibit the action of RNA polymerase.[A191400] The duration of action is moderate, as it is given once daily.[L13239] Patients should be counselled regarding the risk of infusion related reactions, elevated transaminases, and potential decreased efficacy when combined with [hydroxychloroquine] or [chloroquine].[L13239]","mechanism_of_action":"Remdesivir is a nucleoside analog that is expected to inhibit the action of RNA polymerase.[A191400] By incorporating into RNA, additional nucleotides cannot be added, terminating RNA transcription.[A191400] Viruses with mutations in RNA polymerase to develop partial resistance to remdesivir have been shown to be less infective.[A191400]","toxicity":"Data regarding overdoses of remdesivir are not readily available.[L13239] Overdoses of other nucleoside analogs like acyclovir can be managed with symptomatic and supportive treatment.[A191472]","metabolism":"Remdesivir is predominantly metabolized to a triphosphate metabolite.[A191379,A191382]","absorption":"A 10mg/kg intravenous dose given to cynomolgus monkeys distributes to the testes, epididymis, eyes, and brain within 4h.[A191379]","half_life":"A 10mg/kg intravenous dose in non human primates has a plasma half life of 0.39h.[A191379] The nucleoside triphosphate metabolite has a half life of 14h in non human primates.[A191379] The nucleoside triphosphate metabolite has a half life of approximately 20 hours in humans.[A191382]","protein_binding":"Data regarding the protein binding of remdesivir is not readily available.","route_of_elimination":"Remdesivir is 74% eliminated in the urine and 18% eliminated in the feces.[L13239] 49% of the recovered dose is in the form of the metabolite [GS-441524], and 10% is recovered as the unmetabolized parent compound.[L13239]","volume_of_distribution":"Data regarding the volume of distribution of remdesivir is not readily available.","clearance":"Data regarding the clearance of remdesivir is not readily available."}
{"drugbank_id":"DB14999","indication":"This drug is indicated to treat relapsing forms of Multiple Sclerosis (MS) in adults, which includes clinically isolated syndrome, relapsing-remitting disease, as well as active secondary progressive disease.[L12081]","pharmacodynamics":"Interferon-beta has antiviral and immunomodulatory effects. It reduces demyelination, the main component of Multiple Sclerosis pathophysiology, reducing the clinical frequency of MS attacks and slowing disease progression.[A191751,A191784,L12096]\r\n\r\nIn vitro studies have shown that beta interferon reduces the replication of certain coronaviruses in lung tissue.[A191874] Retrospective studies using combinations of [mycophenolate mofetil] and beta interferon showed improved survival against MERS-CoV, the virus that causes Middle Eastern Respiratory Syndrome (MERS). [A191871]","mechanism_of_action":"Part of the pathophysiology of MS is immune cell activation in addition to degradation of the blood\u001abrain barrier (BBB), resulting in both neural demyelination and axon injury. Immunomodulating drugs such as interferon-beta decrease the inflammation that results in demyelination of nerves.  Binding of interferon-beta to type 1 interferon receptors induces a series of beneficial transcriptional JAK/STAT pathway changes. This decreases antigen presentation as well as the proliferation of inflammatory T-cells, reducing the inflammation associated with MS. It also changes the expression of cytokine and matrix metalloproteinase (MMP).[A191751,A191814] \r\n\r\n\r\n\r\n","toxicity":"LD50 information for beta interferon is not readily available in the literature.\r\n\r\nOverdose information\r\n\r\nFollowing an overdose with a very high dose of beta interferon, one patient described in a case report experienced a modest rise in body temperature with diffuse limb and truncal erythema. The symptoms resolved within 24 hours.  Biochemical and hematologic parameters were nonremarkable after the overdose.[A191871] In the case of an overdose, discontinue beta interferon and resume when the patient has returned to baseline function.","metabolism":"Data regarding the metabolism of beta interferon is not readily available in the literature.","absorption":"Beta interferon has a bioavailability of about 30% after subcutaneous or intramuscular administration, demonstrating peak serum concentrations within several hours of a dose. Peak interferon beta-1b concentrations are achieved between 1-8 hours post-dose, measuring about 40 IU/mL.[L12081] After injection, it is absorbed mainly by the lymphatic route.[A191859] Prescribing information for interferon beta-1b indicates a bioavailability of 50%.[L12096] Concentrations of beta interferon are detectable in the circulation 1-2 to days after administration.[A191859]","half_life":"The mean terminal elimination half-life of interferon-beta varies from 8 minutes to about 4 hours.[A191859,L12081]","route_of_elimination":"Beta interferon is excreted by hepatic and renal pathways, with renal pathways accountable for about 40% of its clearance.[A191859]","volume_of_distribution":"The average state volume of distribution for beta interferon is 0.25 L/kg to 2.88 L/kg.[L102081,L12096] Another reference mentions a volume of distribution of 120 L.[A191859] Beta interferon is distributed throughout the body after extravasation across the vascular wall into the tissue after injection. It likely does not cross the blood-brain barrier, and it is unclear whether beta interferon crosses the placenta.[A191859]","clearance":"Average serum clearance in a pharmacokinetic study of beta-interferon 1b ranged from 9.4 mL/min\u001akg-1 to 28.9 mL/min\u001akg-1.[L12096] Another study revealed a clearance ranging between 0.3 to 1.4 L/h/kg.[A191859]"}
{"drugbank_id":"DB15622","indication":"Triazavirin was developed in Russia as a potential treatment of Influenza A and B infections.[A191706]","mechanism_of_action":"Triazavirin is a guanosine nucleotide analog that inhibits RNA synthesis.[A191916,L12165]","toxicity":"The intraperitoneal LD<sub>50<\/sub> of triazavirin in mice is 1400\u001a120mg/kg in mice and the intragastric LD<sub>50<\/sub> is 2200\u001a96mg/kg.[A191706]\r\n\r\nPatients experiencing an overdose may present with nausea, vomiting, dyspepsia, and stomach pain.[L12165] Treat overdose with symptomatic and supportive treatment, which may include discontinuation of treatment.[L12165]","metabolism":"Data regarding the metabolism of triazavirin is not readily available.","absorption":"In rabbits, intragastric triazavirin reaches a C<sub>max<\/sub> of 1.1\u001a0.1mg/L, with a T<sub>max<\/sub> of 0.40\u001a0.16h, and an AUC of 3.10\u001a0.8mg\\*h/L.[A191706] In rabbits, intravenous triazavirin has an AUC of 1.2\u001a0.3mg\\*h/L.[A191706]\r\n\r\nIn humans, triazavirin reaches a C<sub>max<\/sub> of 4.8\u001ag/mL, with a T<sub>max<\/sub> of 1-1.5h, and an AUC of 12.8\u001ag\u001ag/h\\*mL.[L12165]","half_life":"In rabbits, intragastric triazavirin has a half life of 1.1\u001a0.1h while intravenous triazavirin has a half life of 0.50\u001a0.09h.[A191706]\r\n\r\nThe half life of triazavirin is 1-1.5h.[L12165]","protein_binding":"Data regarding the protein binding of triazavirin is not readily available.","route_of_elimination":"Data regarding the route of elimination of triazavirin is not readily available.","volume_of_distribution":"In rabbits, intragastric triazavirin has a volume of distribution of 83.5\u001a19.2L/kg while intravenous triazavirin has a volume of distribution of 1.2\u001a0.3L/kg.[A191706]","clearance":"In rabbits, intragastric triazavirin has a clearance of 37.0\u001a11.2L/h\\*kg while intravenous triazavirin has a clearance of 14.0\u001a3.7L/h\\*kg.[A191706]\r\n\r\nThe clearance of triazavirin is 246mL/min.[L12165]"}
{"drugbank_id":"DB15623"}
{"drugbank_id":"DB15654"}
{"drugbank_id":"DB15655"}
{"drugbank_id":"DB15656"}
{"drugbank_id":"DB15660","indication":"N4-hydroxycytidine and its prodrug [EIDD-2801] is being studied for its activity against a number of viral infections including influenza, MERS-CoV, and SARS-CoV-2.[A193014, A193029]","mechanism_of_action":"N4-hydroxycytidine is phosphorylated in tissue to the active 5\u001a-triphosphate form, which is incorporated into the genome of new virions, resulting in the accumulation of inactivating mutations, known as viral error catastrophe.[A193011,A193029] A [remdesivir] resistant mutant mouse hepatitis virus has also been shown to have increased sensitivity to N4-hydroxycytidine.[A193014]","toxicity":"Data regarding overdose of N4-hydroxycytidine is not readily available. The therapeutic index of N4-hydroxycytidine against a clinical isolate of SARS-CoV-2 is expected to be >100, with an _in vitro_ IC<sub>50<\/sub> of 0.3\u001aM and a CC<sub>50<\/sub> of >10\u001aM.[A193014]","metabolism":"N4-hydroxycytidine distributes into tissues where it is is phosphorylated to the 5'-triphosphate form.[A193026]","absorption":"N4-hydroxycytidine is orally bioavailable in mice[A193011] but poorly bioavailable in non-human primates.[A193026]"}
{"drugbank_id":"DB15661","indication":"[N4-hydroxycytidine] and its prodrug EIDD-2801 is being studied for its activity against a number of viral infections including influenza, MERS-CoV, and SARS-CoV-2.[A193014, A193029]","mechanism_of_action":"EIDD-2801 is hydrolyzed _in vivo_ to N4-hydroxycytidine, which is phosphorylated in tissue to the active 5\u001a-triphosphate form, and incorporated into the genome of new virions, resulting in the accumulation of inactivating mutations, known as viral error catastrophe.[A193011,A193029] A [remdesivir] resistant mutant mouse hepatitis virus has also been shown to have increased sensitivity to N4-hydroxycytidine.[A193014]","metabolism":"EIDD-2801 is hydrolyzed to [N4-hydroxycytidine], which distributes into tissues.[A193026] Once inside cells, N4-hydroxycytidine is phosphorylated to the 5'-triphosphate form.[A193026]","absorption":"EIDD-2801 is orally bioavailable in non-human primates.[A193026]"}
{"drugbank_id":"DB15686","mechanism_of_action":"GS-441524 is phosphorylated 3 times to form the active nucleoside triphosphate, which is incorporated into the genome of virions, terminating its replication.[A203057]","metabolism":"GS-441524 is phosphorylated 3 times to form the active nucleoside triphosphate.[A203057]","absorption":"GS-441524 has been found to transport poorly into cells compared to remdesivir.[A203057,A203072,A191427]"}
{"drugbank_id":"DB15687"}
{"drugbank_id":"DB15688"}
{"drugbank_id":"DB15691"}
{"drugbank_id":"DB15692"}
{"drugbank_id":"DB15693"}