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Metabolism of a new HIV-1 reverse transcriptase inhibitor, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (L-696,229), in rat and liver slices.
Balani SK; Pitzenberger SM; Kauffman LR; Arison BH; Ramjit HG; Goldman
May 30, 1993
Drug Metab Dispos. 1992 Nov-Dec;20(6):869-76. Unique Identifier :

L-696,229 is a potent and specific inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and is currently undergoing clinical evaluation. In vivo metabolism in rats was investigated using an intravenous bolus dose of 5 mg/kg [3H]L-696,229. The amount of radioactivity eliminated in bile and urine over a period of 6 hr was 60 and 22%, respectively. Radiochromatographic analysis of the bile and urine showed that L-696,229 was metabolized rapidly and completely to several common metabolites. Sequential oxidation at the alpha-position of the 5-ethyl group to an acetyl moiety, aromatic hydroxylation of the benzoxazole group (position C4', C6', or C7'), and subsequent sulfate conjugation were the major metabolic pathways as determined by the application of enzymatic hydrolysis, FAB-MS, and 1H- and 13C-NMR spectroscopies. The in vitro metabolism of this 2-pyridinone derivative with rat liver slices resulted primarily in hydroxylation at the 6-methyl and 5-ethyl groups. The 6-hydroxymethyl- and 5-alpha-hydroxyethyl analogs were also inhibitors of HIV-1 reverse transcriptase.

Animal Antiviral Agents/*PHARMACOKINETICS Benzoxazoles/*PHARMACOKINETICS HIV-1/DRUG EFFECTS/*ENZYMOLOGY In Vitro Liver/*METABOLISM Male Pyridones/*PHARMACOKINETICS Rats Rats, Sprague-Dawley RNA-Directed DNA Polymerase/*ANTAGONISTS & INHIB JOURNAL ARTICLE

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