Excretion and metabolism of lersivirine (5-{[3,5-diethyl-1-(2-hydroxyethyl)(3,5-14C2)-1H-pyrazol-4-yl]oxy}benzene-1,3-dicarbonitrile), a next-generation non-nucleoside reverse transcriptase inhibitor, after administration of [14C]Lersivirine to healthy volunteers

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Manoli VourvahisRobert R Labadie

Abstract

Lersivirine [UK-453,061, 5-((3,5-diethyl-1-(2-hydroxyethyl)(3,5-14C2)-1H-pyrazol-4-yl)oxy)benzene-1,3-dicarbonitrile] is a next-generation non-nucleoside reverse transcriptase inhibitor, with a unique binding interaction within the reverse transcriptase binding pocket. Lersivirine has shown antiviral activity and is well tolerated in HIV-infected and healthy subjects. This open-label, Phase I study investigated the absorption, metabolism, and excretion of a single oral 500-mg dose of [14C]lersivirine (parent drug) and characterized the plasma, fecal, and urinary radioactivity of lersivirine and its metabolites in four healthy male volunteers. Plasma C(max) for total radioactivity and unchanged lersivirine typically occurred between 0.5 and 3 h postdose. The majority of radioactivity was excreted in urine (approximately 80%) with the remainder excreted in the feces (approximately 20%). The blood/plasma ratio of total drug-derived radioactivity [area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUC(inf))] was 0.48, indicating that radioactive material was distributed predominantly into plasma. Lersivirine was extensively metabolized, primarily by UDP glucuronosyltransferase- and cytoch...Continue Reading

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Citations

Sep 2, 2010·Journal of Medicinal Chemistry·Fraser F FlemingBrian C Shook
Nov 30, 2011·Antimicrobial Agents and Chemotherapy·Manoli VourvahisJohn Davis
Sep 7, 2013·Journal of the International AIDS Society·Iris UsachJosé-Esteban Peris
Oct 17, 2013·Expert Opinion on Investigational Drugs·Martin Platten, Gerd Fätkenheuer
Jun 12, 2012·Drug and Alcohol Dependence·Manoli VourvahisMargaret Tawadrous
Oct 26, 2016·Cancer Chemotherapy and Pharmacology·Brian F KieselJulie L Eiseman
Nov 25, 2017·Nature Communications·Joanne TanAndrei K Yudin
Aug 15, 2013·Organic & Biomolecular Chemistry·Márió GyurisIván Kanizsai
Dec 1, 2019·Nature Communications·Geoffrey HutinetValérie de Crécy-Lagard
Apr 21, 2012·Journal of Acquired Immune Deficiency Syndromes : JAIDS·Manoli VourvahisJohn Davis

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