PMID: 9660845Jul 14, 1998Paper

Metabolism of delavirdine, a human immunodeficiency virus type-1 reverse transcriptase inhibitor, by microsomal cytochrome P450 in humans, rats, and other species: probable involvement of CYP2D6 and CYP3A

Drug Metabolism and Disposition : the Biological Fate of Chemicals
R L VoormanM J Ackland

Abstract

The metabolism of delavirdine was examined using liver microsomes from several species with the aim of comparing metabolite formation among species and characterizing the enzymes responsible for delavirdine metabolism. Incubation of 10 microM [14C]delavirdine with either an S9 fraction from human jejunum or liver microsomes from rat, human, dog, or monkey followed by high pressure liquid chromatography analysis showed qualitatively similar metabolite profiles among species with the formation of three significant metabolites. The major metabolite was desalkyl delavirdine; however, the identity of MET-7 and MET-7a (defined by high pressure liquid chromatography elution) could not be unambiguously established, but they seem to be related pyridine hydroxy metabolites, most likely derived from 6'-hydroxylation of the pyridine ring. The apparent KM for delavirdine desalkylation activity ranged from 4.4 to 12.6 microM for human, rat, monkey, and dog microsomes, whereas Vmax ranged from 0.07 to 0.60 nmol/min/mg protein, resulting in a wide range of intrinsic clearance (6-135 microL/min/mg protein). Delavirdine desalkylation by microsomes pooled from several human livers was characterized by a KM of 6.8 +/- 0.8 microM and Vmax of 0. 44 ...Continue Reading

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