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.
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 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.
Vourvahis
Manoli
M
Pfizer Global R&D, 50 Pequot Avenue, New London, CT 06320, USA. manoli.vourvahis@pfizer.com
Gleave
Michelle
M
Nedderman
Angus N R
AN
Hyland
Ruth
R
Gardner
Iain
I
Howard
Martin
M
Kempshall
Sarah
S
Collins
Claire
C
LaBadie
Robert
R
D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D019540:Area Under Curve; D055162:Biocatalysis; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003640:Dealkylation; D005243:Feces / Q000737:chemistry; D005966:Glucuronidase / Q000378:metabolism; D020719:Glucuronides / Q000032:analysis / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D006900:Hydroxylation; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008875:Middle Aged; D015394:Molecular Structure; D009570:Nitriles / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D010084:Oxidation-Reduction; D011720:Pyrazoles / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D011994:Recombinant Proteins / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D013431:Sulfates / Q000378:metabolism; D053719:Tandem Mass Spectrometry
D019380:Anti-HIV Agents; D020719:Glucuronides; D009570:Nitriles; D011720:Pyrazoles; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D013431:Sulfates; C531151:UK 453,061; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D005966:Glucuronidase