0090-9556/97/2507-0814-0827$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 7

Identification of the Metabolites of the HIV-1 Reverse Transcriptase Inhibitor Delavirdine in Monkeys

Mayland Chang, Virendra K. Sood, David A. Kloosterman, Michael J. Hauer, Paul E. Fagerness, Phillip E. Sanders, and J. James Vrbanac

Drug Metabolism Research (M.C., V.K.S., M.J.H., P.E.F., P.E.S, J.J.V.) and Structural, Analytical and Medicinal Chemistry (D.A.K.), Pharmacia & Upjohn, Inc.

Delavirdine mesylate (U-90152T) is a highly specific nonnucleoside HIV-1 reverse transcriptase inhibitor currently under development for the treatment of AIDS. The metabolism of delavirdine was investigated in male and female cynomolgus monkeys after oral administration of [¹⁴C-carboxamide]delavirdine mesylate at single doses of 80 mg/kg and multiple doses of 160 to 300 mg/kg/day. Desalkyl delavirdine was the major metabolite in circulation. In urine, desalkyl delavirdine accounted for nearly half of the radioactivity, with despyridinyl delavirdine and conjugates 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 delavirdine, and conjugates of desalkyl delavirdine as significant components. In addition, several minor metabolites were observed in urine and bile of delavirdine treated monkeys. The metabolism of delavirdine in the monkey was extensive and involved N-desalkylation, hydroxylation at the C-4 and C-6 positions of the pyridine ring, hydroxylation at the C-4 position of the indole ring, pyridine ring-cleavage, N-glucuronidation of the indole ring, and amide bond cleavage as determined by MS and/or one-dimensional and two-dimensional NMR spectroscopies. Phase II biotransformations included glucuronidation, sulfation, and -N-acetylglucosaminidation. The identification of the N-linked -N-acetylglucosamine and 4-O-glucuronide metabolites of delavirdine represents novel biotransformation pathways.