Pharmacokinetics of [C-14]abacavir, a human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, administered in a single oral doseto HIV-1-infected adults: a mass balance study

Abacavir (1592U89) {( - )-(1S, 4R)-4-[2-amino-6-(cyclopropylamino) -9H-puri n-9-yl]-2-cyclopentene-1-methanol} is a 2'-deoxyguanosine analogue with pot ent activity against human immunodeficiency virus (HIV) type 1. To determin e the metabolic profile, routes of elimination, and total recovery of abaca vir and metabolites in humans, we undertook a phase I mass balance study in which six HIV-infected male volunteers ingested a single 600-mg oral dose of abacavir including 100 mu Ci of [C-14]abacavir, The metabolic dispositio n of the drug was determined through analyses of whole-blood, plasma, urine , and stool samples, collected for a period of up to 10 days postdosing, an d of cerebrospinal fluid (CSF), collected up to 6 h postdosing, The radioac tivity from abacavir and its two major metabolites, a 5'-carboxylate (2269W 93) and a 5'-glucuronide (361W94), accounted for the majority (92%) of radi oactivity detected in plasma. Virtually all of the administered dose of rad ioactivity (99%) was recovered, with 83% eliminated in urine and 16% elimin ated in feces. Of the 83% radioactivity dose eliminated in the urine, 36% w as identified as 361W94, 30% was identified as 2269W93, and 1.2% was identi fied as abacavir; the remaining 15.8% was attributed to numerous trace meta bolites, of which <1% of the administered radioactivity was 1144U88, a mino r metabolite. The peak concentration of abacavir in CSF ranged from 0.6 to 1.4 mu g/ml, which is 8 to 20 times the mean 50% inhibitory concentration f or HIV clinical isolates in vitro (0.07 mu g/ml). In conclusion, the main r oute of elimination for oral abacavir in humans is metabolism, with <2% of a dose recovered in urine as unchanged drug. The main route of metabolite e xcretion is renal, with 83% of a dose recovered in urine. Two major metabol ites, the 5'-carboxylate and the 5'-glucuronide, were identified in urine a nd, combined, accounted for 66% of the dose. Abacavir showed significant pe netration into CSF.