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Metabolic Disposition and Pharmacokinetics of [ 14 C]‐Amprenavir, a Human Immunodeficiency Virus Type 1 (HIV‐1) Protease Inhibitor, Administered As a Single Oral Dose to Healthy Male Subjects
Author(s) -
Sadler Brian M.,
Chittick Gregory E.,
Polk Ronald E.,
Slain Douglas,
Kerkering Thomas M.,
Studenberg Scott D.,
Lou Yu,
Moore Katy H. P.,
Woolley Joseph L.,
Stein Daniel S.
Publication year - 2001
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/00912700122010249
Subject(s) - amprenavir , urine , feces , metabolite , pharmacokinetics , pharmacology , chemistry , medicine , biology , microbiology and biotechnology , biochemistry , protease , hiv 1 protease , enzyme
The objective of this study was to determine the metabolic profile, routes of elimination, and total recovery of amprenavir and its metabolites after a single oral dose of [ 14 C]‐amprenavir. Six healthy male subjects each received a single oral 630 mg dose of amprenavir containing 95.76 μCi of [ 14 C]‐amprenavir in this Phase I mass balance study. The metabolic disposition of amprenavir was determined through analyses of radiocarbon in whole blood, plasma, urine, and stool samples, collected for a period of 10 to 17 days postdosing. Cerebral spinal fluid (CSF) sampling was conducted on day 1. The ratio of unchanged amprenavir AUC0→∞ to plasma radiocarbon was 27%, suggesting that most of the radiocarbon was metabolites. The median total recovery of the administered dose of radiocarbon was 89% (range: 66%‐93%), with 75% (range: 56%‐80%) recovered in the feces and 14% (range: 10%‐17%) in the urine. Most of the recovered radiocarbon in the feces and urine was excreted within 240 and 48 hours postdose, respectively. Of the 75% of the radiocarbon dose recovered in the feces, 62% wasidentified as a metabolite resulting from dioxidation of the tetrahydrofuran ring (GW549445X) and 32% as a metabolite resulting from subsequent oxidation of the p‐aniline sulfonate group (GW549444X). Unchanged amprenavir was below the limit of quantitation in feces and urine. Therefore, approximately 94% of the dose excreted in the feces was accounted for by these two metabolites. Concentrations of radiocarbon in the CSF were below the limit of quantitation in 5 of 6 subjects sampled. In summary, oral amprenavir is extensively metabolized in humans, with concentrations of unchanged drug below the limits of quantitation in urine and feces. The majority (75%) of administered radiocarbon was excreted in feces.