DISPOSITION OF INDINAVIR, A POTENT HIV-1 PROTEASE INHIBITOR, AFTER ANORAL DOSE IN HUMANS

Indinavir, -4-(3-pyridylmethyl)piperazino]-4(S)-hydroxy-2(R)- phenylme thylpentanamide (L-735,524,MK-639, and Crixivan), is a potent and spec ific inhibitor of the HIV-1 protease for the treatment of AIDS. Dispos ition of [C-14]indinavir was investigated in six healthy subjects afte r single oral administration of 400 mg. AUG, C-max, and T-max values f or indinavir were 492 mu M . min, 4.7 mu M, and 50 min, respectively. The AUC value for the total radioactivity in plasma was 1.9 times high er than that of indinavir, indicating the presence of metabolites. The major excretory route was through feces, and the minor through urine. Mean recovery of radioactivity in the feces was 83.4%. In the urine, mean recoveries of the total radioactivity and unchanged indinavir wer e 18.7% and 11.0% of the dose, respectively. HPLC radioactivity and LC -MS/MS analyses of urine showed the presence of indinavir and low leve ls of quaternary pyridine N-glucuronide (M1), 2',3'-trans-dihydroxyind anylpyridine N-oxide (M2), 2',3'-trans-dihydroxyindan (M3) and pyridin e N-oxide (M4a) analogs, and despyridylmethyl analogs of M3 (M5) and i ndinavir (M6). M5 and Mg were the major metabolites in urine. The meta bolic profile in plasma was similar to that in urine. Quantitatively, the metabolites in feces accounted for >47% of the dose, which along w ith the urinary excretion of similar to 19%, suggested that the absorp tion of the drug was appreciable. In the feces, radioactivity was pred ominantly due to M3, M5, Mg, and the parent compound. Thus, in urine a nd feces, the prominent metabolic pathways were oxidations end oxidati ve N-dealkylations, Excretion of the quaternary N-glucuronide metaboli te in the urine, which is a minor metabolite in human, was specific to primates.