Document 0879
 DOCN  M9470879
 TI    Metabolism of 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2
       (1H)-one (L-696,229), an HIV-1 reverse transcriptase inhibitor, by rat
       liver slices and in humans.
 DT    9409
 AU    Balani SK; Kauffman LR; Arison BH; Olah TV; Goldman ME; Varga SL;
       O'Brien JA; Ramjit HG; Rooney CS; Hoffman JM; et al; Department of Drug
       Metabolism, Merck Research Laboratories, West; Point, PA 19486.
 SO    Drug Metab Dispos. 1994 Mar-Apr;22(2):200-5. Unique Identifier :
       AIDSLINE MED/94283115
 AB    Healthy subjects were administered single oral doses of 800 mg or 400 mg
       3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-o ne
       (L-696,229), a nonnucleoside inhibitor of the human immunodeficiency
       virus-type 1 (HIV-1) reverse transcriptase (RT). Plasma or urine samples
       were collected over a period of 48 hr. Pooled plasma (0.5-6 hr) and
       urine (0-24 hr) samples were analyzed by HPLC-UV and HIV-1 RT inhibition
       assay using poly rC.dG as a template primer. The parent compound and
       several common metabolites were detected in both samples. The metabolic
       profiles were also similar to those obtained from a rat liver slice
       incubation with [3H]L-696,229. The in vitro metabolites were identified
       by NMR and MS as 5 alpha-hydroxyethyl- (major), 5,6-dihydrodiol-,
       6'-hydroxy-, 6-hydroxymethyl-, and 5-vinyl analogs, and a benzoxazole
       ring hydrolysis product. Most of the significant metabolites in human
       plasma and urine were found to be identical to the in vitro metabolites,
       as established by HPLC-UV and MS. Hydrolysis of the plasma and urine
       with beta-glucuronidase/sulfatase indicated the presence of significant
       amounts of conjugates of the parent compound and 5 alpha-hydroxyethyl
       metabolite. Most of the other primary metabolites were also present in
       conjugated forms, albeit in small quantities. In addition, two secondary
       metabolites were isolated and identified from the hydrolyzed urine as
       5-acetyl-6'-hydroxy- and 5 alpha-hydroxyethyl-6-hydroxymethyl-
       analogs.(ABSTRACT TRUNCATED AT 250 WORDS)
 DE    Administration, Oral  Animal
       Benzoxazoles/PHARMACOLOGY/*PHARMACOKINETICS  Biotransformation
       Chromatography, High Pressure Liquid  Human  Hydrolysis
       HIV-1/*ENZYMOLOGY  In Vitro  Liver/*METABOLISM  Male  Nuclear Magnetic
       Resonance  Pyridones/PHARMACOLOGY/*PHARMACOKINETICS  Rats  Rats,
       Sprague-Dawley  Reverse Transcriptase/*ANTAGONISTS & INHIB
       Spectrophotometry, Ultraviolet  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).