IDENTIFICATION OF THE METABOLITES OF THE HIV-1 REVERSE-TRANSCRIPTASE INHIBITOR DELAVIRDINE IN MONKEYS

Delavirdine mesylate (U-90152T) is highly specific nonnucleoside HIV-1 reverse transcriptase inhibitor currently under development For the t reatment of AIDS. The metabolism of delavirdine was investigated in ma le and female cynomolgus monkeys after oral administration of [C-14-ca rboximide]delavirdine mesylate at single doses of 80 mg/kg and multipl e doses of 160 to 300 mg/kg/day. Desalkyl delavirdine was the major me tabolite in circulation. In urine, desalkyl delavirdine accounted for nearly half of the radioactivity, with despyridinyl delavirdine and co njugates of desalkyl delavirdine accounting for most of the remaining radioactivity. Bile was mostly composed of desalkyl delavirdine and 6' -O-glucuronide delavirdine, with parent drug, 4-O-glucuronide delavird ine, and conjugates of desalkyl delavirdine as significant components. In addition, several minor metabolites were observed in urine and bil e of delavirdine treated monkeys. The metabolism of delavirdine in the monkey was extensive and involved N-desalkylation, hydroxylation at t he C-4' and C-6' positions of the pyridine ring, hydroxylation at the C-4 position of the indole ring, pyridine ring-cleavage, N-glucuronida tion of the indole ring, and amide bond cleavage as determined by MS a nd/or one-dimensional and two-dimensional NMR spectroscopies. Phase II biotransformations included glucuronidation, sulfation, and beta-N-ac etylglucosaminidation. The identification of the N-linked beta-N-acety lglucosamine and 4-O-glucuronide metabolites of delavirdine represents novel biotransformation pathways.