TY - JOUR T1 - Excretion and Metabolism of Lersivirine (5-{[3,5-Diethyl-1-(2-hydroxyethyl)(3,5-<sup>14</sup>C<sub>2</sub>)-1<em>H</em>-pyrazol-4-yl]oxy}benzene-1,3-dicarbonitrile), a Next-Generation Non-Nucleoside Reverse Transcriptase Inhibitor, after Administration of [<sup>14</sup>C]Lersivirine to Healthy Volunteers JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 789 LP - 800 DO - 10.1124/dmd.109.031252 VL - 38 IS - 5 AU - Manoli Vourvahis AU - Michelle Gleave AU - Angus N. R. Nedderman AU - Ruth Hyland AU - Iain Gardner AU - Martin Howard AU - Sarah Kempshall AU - Claire Collins AU - Robert LaBadie Y1 - 2010/05/01 UR - http://dmd.aspetjournals.org/content/38/5/789.abstract N2 - 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 Cmax for total radioactivity and unchanged lersivirine typically occurred between 0.5 and 3 h postdose. The majority of radioactivity was excreted in urine (∼80%) with the remainder excreted in the feces (∼20%). The blood/plasma ratio of total drug-derived radioactivity [area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUCinf)] was 0.48, indicating that radioactive material was distributed predominantly into plasma. Lersivirine was extensively metabolized, primarily by UDP glucuronosyltransferase- and cytochrome P450-dependent pathways, with 22 metabolites being identified in this study. Analysis of precipitated plasma revealed that the lersivirine-glucuronide conjugate was the major circulating component (45% of total radioactivity), whereas unchanged lersivirine represented 13% of total plasma radioactivity. In vitro studies showed that UGT2B7 and CYP3A4 are responsible for the majority of lersivirine metabolism in humans. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -