Characterisation of the absorption, distribution, metabolism, excretion and mass balance of doravirine, a non-nucleoside reverse transcriptase inhibitor in humans.
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Sanchez RI, Fillgrove KL, Yee KL, Liang Y, Lu B, Tatavarti A, Liu R, Anderson MS, Behm MO, Fan L, Li Y, Butterton JR, Iwamoto M, Khalilieh SG
Characterisation of the absorption, distribution, metabolism, excretion and mass balance of doravirine, a non-nucleoside reverse transcriptase inhibitor in humans.
Xenobiotica. 2018 Mar 28:1-11. doi: 10.1080/00498254.2018.1451667.
- PubMed ID
- 29557716 [ View in PubMed]
- Abstract
Absorption, distribution, metabolism and elimination of doravirine (MK-1439), a novel non-nucleoside reverse transcriptase inhibitor, were investigated. Two clinical trials were conducted in healthy subjects: an oral single dose [(14 )C]doravirine (350 mg, approximately 200 microCi) trial (n = 6) and an intravenous (IV) single-dose doravirine (100 microg) trial (n = 12). In vitro metabolism, protein binding, apparent permeability and P-glycoprotein (P-gp) transport studies were conducted to complement the clinical trials. Following oral [(14 )C]doravirine administration, all of the administered dose was recovered. The absorbed dose was eliminated primarily via metabolism. An oxidative metabolite (M9) was the predominant metabolite in excreta and was the primary circulating metabolite (12.9% of circulating radioactivity). Following IV administration, doravirine clearance and volume of distribution were 3.73 L/h (95% confidence intervals (CI) 3.09, 4.49) and 60.5 L (95% CI 53.7, 68.4), respectively. In vitro, doravirine is not highly bound to plasma proteins (unbound fraction 0.24) and has good passive permeability. The metabolite M9 was generated by cytochrome P450 3A (CYP3A)4/5-mediated oxidation. Doravirine was a P-gp substrate but P-gp efflux is not expected to play a significant role in limiting doravirine absorption or to be involved in the elimination of doravirine. In conclusion, doravirine is a low clearance drug, primarily eliminated by CYP3A-mediated metabolism.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Doravirine Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Doravirine Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails