Identification of cytochrome P450 isozymes involved in metabolism of theα1-adrenoceptor blocker tamsulosin in human liver microsomes
| Autor: | S Higuchi, Michael Hall, S Oishi, T Watanabe, S G Wood, L. F. Chasseaud, H Matsushima, Hidetaka Kamimura |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Tamsulosin
CYP2D6 medicine.medical_specialty Health Toxicology and Mutagenesis Metabolite Pharmacology Paeonia Toxicology Biochemistry Isozyme Antibodies chemistry.chemical_compound Cytochrome P-450 Enzyme System Microsomes Internal medicine Glycyrrhiza medicine Cytochrome P-450 Enzyme Inhibitors Humans Enzyme Inhibitors Adrenergic alpha-Antagonists Biotransformation Sulfonamides CYP3A4 biology Sparteine Cytochrome P450 General Medicine Dextromethorphan Isoenzymes Drug Combinations Endocrinology chemistry Adrenergic alpha-1 Receptor Antagonists Microsomes Liver biology.protein Microsome NADP Drugs Chinese Herbal medicine.drug |
| Zdroj: | Xenobiotica. 28:909-922 |
| ISSN: | 1366-5928 0049-8254 |
| DOI: | 10.1080/004982598238985 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|