PT  - JOURNAL ARTICLE
AU  - S K Balani
AU  - S M Pitzenberger
AU  - L R Kauffman
AU  - B H Arison
AU  - H G Ramjit
AU  - M E Goldman
AU  - J A O'Brien
AU  - J D King
AU  - J M Hoffman
AU  - C S Rooney
TI  - 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.
DP  - 1992 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 869--876
VI  - 20
IP  - 6
4099  - http://dmd.aspetjournals.org/content/20/6/869.short
4100  - http://dmd.aspetjournals.org/content/20/6/869.full
SO  - Drug Metab Dispos1992 Nov 01; 20
AB  - 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.