Metabolic disposition and pharmacokinetics of [C-14]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjects

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 [C-14]-amprenavir. Six healthy male subjects each rec eived a single oral 630 mg dose of amprenavir containing 95.76 mu Ci of [C- 14]-amprenavir in this Phase I mass balance study. The metabolic dispositio n of amprenavir was determined through analyses of radiocarbon in whole blo od, plasma, urine, and stool samples, collected for a period of 30 to 17 da ys postdosing. Cerebral spinal fluid (CSF) sampling was conducted on day 1. The ratio of unchanged amprenavir AUC(0 --> infinity),, to plasma radiocar bon was 27%, suggesting that most of the radiocarbon was metabolites. The m edian 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% was identified as a metabolite resulting from dioxidation of the tetrahydrofuran ring (GW54944 5X) and 32% as a metabolite resulting from subsequent oxidation of the p-an iline sulfonate group (GW549444X). Unchanged amprenavir was below the limit of quantitation in feces and urine. Therefore, approximately 94% of the do se excreted in the feces was accounted for by these two metabolites. Concen trations of radiocarbon in the CSF were below the limit of quantitation in 5 of 6 subjects sampled. In summary, oral amprenavir is extensively metabol ized in humans, with concentrations of unchanged drug below the limits of q uantitation in urine and feces. The majority (75%) of administered radiocar bon was excreted in feces. (C) 2001 the American College of Clinical Pharma cology.