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

• Published in: Drug metabolism and disposition Vol. 25; no. 7; pp. 814 - 827
• Main Authors: CHANG, M, SOOD, V. K, KLOOSTERMAN, D. A, HAUER, M. J, FAGERNESS, P. E, SANDERS, P. E, VRBANAC, J. J
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-07-1997
• Subjects: AIDS/HIV; Animals; Anti-HIV Agents - pharmacokinetics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Bile - chemistry; Bile - metabolism; Biological and medical sciences; Biotransformation; Chromatography, High Pressure Liquid; Delavirdine; Female; HIV-1 - enzymology; Hydrolysis; Indoles - pharmacokinetics; Macaca fascicularis; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Medical sciences; Pharmacology. Drug treatments; Piperazines - pharmacokinetics; Reverse Transcriptase Inhibitors - pharmacokinetics; Spectrophotometry, Ultraviolet; Biological fluid; RNA-directed DNA polymerase; Monkey; Multiple dose; Primates; Lentivirinae; Antiviral; Antiinfectious; Urine; Enzyme; Transferases; Single dose; Elimination; Oral administration; Retroviridae; Enzyme inhibitor; Metabolism; Delavirdine; Virus; Nucleotidyltransferases; Vertebrata; Mammalia; Animal; Human immunodeficiency virus; Pharmacokinetics; Bile
• ISSN: 0090-9556; 1521-009X

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 [ 14 C-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 β- N -acetylglucosaminidation. The identification of the N -linked β- N -acetylglucosamine and 4- O -glucuronide metabolites of delavirdine represents novel biotransformation pathways.