Metabolic disposition and pharmacokinetics of [14C]-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 [14C]-amprenavir. Six healthy male subjects each received a single oral 630 mg dose of amprenavir containing 95.76 microCi of [14C]-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-->infinity 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% was identified 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.
Sadler
B M
BM
Division of Clinical Pharmacology, Glaxo Wellcome, Inc., Research Triangle Park, NC 27709, USA.
Chittick
G E
GE
Polk
R E
RE
Slain
D
D
Kerkering
T M
TM
Studenberg
S D
SD
Lou
Y
Y
Moore
K H
KH
Woolley
J L
JL
Stein
D S
DS
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044383:Black People; D001944:Breath Tests / Q000379:methods; D002219:Carbamates; D002250:Carbon Radioisotopes; D005500:Follow-Up Studies; D005663:Furans; D018023:HIV Seronegativity; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044465:White People
D019380:Anti-HIV Agents; D002219:Carbamates; D002250:Carbon Radioisotopes; D005663:Furans; D011480:Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir