Metabolism of the human immunodeficiency virus type 1 reverse transcriptase inhibitor delavirdine in rats.

Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.

Metabolism of the human immunodeficiency virus type 1 reverse transcriptase inhibitor delavirdine in rats.

Drug Metab Dispos. 1997 Feb;25(2):228-42. Unique Identifier : AIDSLINE MED/97180836
Chang M; Sood VK; Wilson GJ; Kloosterman DA; Sanders PE; Hauer MJ; Fagerness PE; Drug Metabolism Research, Pharmacia & Upjohn, Inc., Kalamazoo, MI; 49007, USA.

Abstract: Delavirdine mesylate (U-90152T) is a highly specific nonnucleoside reverse transcriptase inhibitor currently under development for the treatment of AIDS. The excretion, disposition, and metabolism of delavirdine were investigated in Sprague-Dawley rats after oral administration of [14C]delavirdine mesylate at single doses ranging from 10 to 250 mg/kg and multiple doses ranging from 20 to 250 mg/kg/day. Excretion studies showed that feces was the major route of elimination, delavirdine was well absorbed (>80%) after a 10 mg/kg single dose, and excretion was dose-dependent. The metabolism of delavirdine in the rat was extensive. The following metabolites were identified (% of dose in rats given 10 and 100 mg/kg, respectively): 6'-hydroxy delavirdine (7.1% and 15.6%) and its glucuronide (12.2% and 6.2%) and sulfate (5.5% and 3.2%) conjugates, despyridinyl delavirdine (12.1% and 11.7%) and its conjugate (13.0% and 11.7%), desalkyl delavirdine (16.5% and 13.4%), and its N-sulfamate, 6'- and 4'-sulfate conjugates (2.9% and 3.9%). Cleavage of the amide bond in delavirdine to give N-isopropylpyridinepiperazine and indole carboxylic acid constituted a minor pathway. Degradation of 6'-hydroxy delavirdine generated despyridinyl delavirdine and the pyridine-ring opened MET-14. The metabolic pathway of delavirdine involved N-desalkylation, pyridine ring hydroxylation, pyridine ring cleavage, and amide bond cleavage.

Keywords: *Anti-HIV Agents/PHARMACOKINETICS *HIV-1/DRUG EFFECTS *Indoles/PHARMACOKINETICS *Piperazines/PHARMACOKINETICS *Reverse Transcriptase Inhibitors/PHARMACOKINETICS
970730
M9771469

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