title: 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.
abstract: 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)
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486.
authors.forename: T
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: L M
authors.initials: LM
authors.lastname: Dwyer
authors.forename: S K
authors.initials: SK
authors.lastname: Balani
authors.forename: A D
authors.initials: AD
authors.lastname: Theoharides
mesh_terms: D000368:Aged; D000818:Animals; D001583:Benzoxazoles / Q000493:pharmacokinetics*; D002648:Child; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D004064:Digestive System / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D011728:Pyridones / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors; D012727:Sex Characteristics; D013237:Stereoisomerism
chemical_list: D001583:Benzoxazoles; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; C076250:L 696229; D003577:Cytochrome P-450 Enzyme System; D054303:HIV Reverse Transcriptase