Identification of cytochrome P450 isozymes involved in metabolism of the alpha1-adrenoceptor blocker tamsulosin in human liver microsomes

Xenobiotica. 1998 Oct;28(10):909-22. doi: 10.1080/004982598238985.

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.

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists*
  • Adrenergic alpha-Antagonists / metabolism*
  • Adrenergic alpha-Antagonists / pharmacokinetics
  • Antibodies / pharmacology
  • Biotransformation
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / immunology
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Combinations
  • Drugs, Chinese Herbal / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Glycyrrhiza
  • Humans
  • Isoenzymes / metabolism
  • Microsomes / metabolism
  • Microsomes, Liver / metabolism*
  • NADP / metabolism
  • Paeonia
  • Sulfonamides / metabolism*
  • Sulfonamides / pharmacokinetics
  • Tamsulosin

Substances

  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Antagonists
  • Antibodies
  • Cytochrome P-450 Enzyme Inhibitors
  • Drug Combinations
  • Drugs, Chinese Herbal
  • Enzyme Inhibitors
  • Isoenzymes
  • Sulfonamides
  • shakuyaku-kanzoh-toh
  • NADP
  • Cytochrome P-450 Enzyme System
  • Tamsulosin