Document 0878
 DOCN  M9470878
 TI    In vitro metabolism of L-696,229, an HIV-1 reverse transcriptase
       inhibitor in rats and humans. Hepatic and extrahepatic metabolism and
       identification of enzymes involved in the hepatic metabolism.
 DT    9409
 AU    Prueksaritanont T; Dwyer LM; Balani SK; Theoharides AD; Department of
       Drug Metabolism, Merck Research Laboratories, West; Point, PA 19486.
 SO    Drug Metab Dispos. 1994 Mar-Apr;22(2):281-8. Unique Identifier :
       AIDSLINE MED/94283127
 AB    The metabolism of L-696,229,
       3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-o ne, a
       potent human immunodeficiency virus-type 1 reverse transcriptase
       inhibitor, by rat liver, lung, gut, and kidney microsomes has been
       studied. L-696,229 was metabolized by rat liver microsomes to several
       products: the 5 alpha-hydroxyethyl (M1); 5,6-dihydrodiol (M2);
       6'-hydroxy (M3); 6-hydroxymethyl (M4); and 5-vinyl (M5) metabolites. For
       these pathways, liver was the most active metabolizing organ, whereas
       lung was the major extrahepatic organ in the drug metabolism. In all
       tissues tested, M1 was the major metabolite. With the exception of M3,
       gender differences in the hepatic formation of all metabolites were
       observed. Enzymes responsible for the hepatic metabolism of L-696,229 in
       rats were also investigated using various enzyme inducers and polyclonal
       antibodies to rat P-450. Treatment of male rats with dexamethasone (DX)
       or phenobarbital (PB) caused significant increases in the hepatic
       formation of the gender-dependent metabolites. Methylcholanthrene (3-MC)
       greatly enhanced the hepatic formation of M1, M3, and M4.
       Immunoinhibition studies suggested that CYP2B1/2 and 2E1 were not
       involved in L-696,229 metabolism, whereas CYP1A was partly responsible
       for the formation of M1 in untreated rats. CYP3A played an important
       role in the formation of M1, M2, M4, and M5 in untreated and DX-treated
       rats. In PB-treated rats, CYP2B1/2 was involved in the increased
       formation of M1 and M4, whereas CYP3A was partly involved in the
       enhanced M2 and M4 formation, and primarily responsible for the
       increased M5 formation.(ABSTRACT TRUNCATED AT 250 WORDS)
 DE    Aged  Animal  Benzoxazoles/*PHARMACOKINETICS  Child  Chromatography,
       High Pressure Liquid  Cytochrome
       P-450/BIOSYNTHESIS/IMMUNOLOGY/METABOLISM  Enzyme Induction/DRUG EFFECTS
       Female  Gastrointestinal System/METABOLISM  Human  HIV-1/*ENZYMOLOGY  In
       Vitro  Liver/ENZYMOLOGY/*METABOLISM  Lung/METABOLISM  Male
       Microsomes/ENZYMOLOGY/METABOLISM  Microsomes,
       Liver/ENZYMOLOGY/METABOLISM  Pyridones/*PHARMACOKINETICS  Rats  Rats,
       Sprague-Dawley  Reverse Transcriptase/*ANTAGONISTS & INHIB  Sex
       Characteristics  Stereoisomers  JOURNAL ARTICLE

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