title: Identification of cytochrome P450 isozymes involved in metabolism of the alpha1-adrenoceptor blocker tamsulosin in human liver microsomes.
abstract: 1. The in vitro human liver metabolism of the alpha1-adrenoceptor blocker tamsulosin was investigated. When 14C-tamsulosin was incubated with human liver microsomes, it was converted to five known urinary metabolites and at least three unknown metabolites. Of the former group, the predominant metabolite was the O-deethylated metabolite (M-1), followed by the o-ethoxyphenoxy acetic acid (AM-1) and the m-hydroxylated metabolite (M-3). 2. There was a good linear relationship between AM-1 formation and testosterone 6beta-hydroxylase activity in microsomes from each of 10 individual donors. The rate of M-1 formation also correlated with the same activity, albeit the correlation curve did not pass through the origin. By contrast, the rates of M-3 and the O-demethylated metabolite (M-4) formation correlated with dextromethorphan O-demethylase activity. 3. Ketoconazole strongly inhibited AM-1 formation and reduced that of M-1 by c. 60%. Immunoinhibition studies using anti-rat antibodies supported these results. The formation of M-3 and M-4 was inhibited by quinidine and sparteine. 4. It is concluded that formation of tamsulosin metabolites, AM-1 and M-1, is catalysed by CYP3A4 whereas that of M-3 and M-4 is catalysed by CYP2D6. However, minor contributions from other CYPs cannot be excluded.
authors.affiliation: Analytical Science Laboratories, Yamanouchi Pharmaceutical Co., Ltd, Shizuoka-ken, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kamimura
authors.forename: S
authors.initials: S
authors.lastname: Oishi
authors.forename: H
authors.initials: H
authors.lastname: Matsushima
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: S
authors.initials: S
authors.lastname: Higuchi
authors.forename: M
authors.initials: M
authors.lastname: Hall
authors.forename: S G
authors.initials: SG
authors.lastname: Wood
authors.forename: L F
authors.initials: LF
authors.lastname: Chasseaud
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism* / Q000493:pharmacokinetics; D000906:Antibodies / Q000494:pharmacology; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006035:Glycyrrhiza; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D029596:Paeonia; D013449:Sulfonamides / Q000378:metabolism* / Q000493:pharmacokinetics; D000077409:Tamsulosin
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000906:Antibodies; D065607:Cytochrome P-450 Enzyme Inhibitors; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D013449:Sulfonamides; C038462:shakuyaku-kanzoh-toh; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D000077409:Tamsulosin