IDENTIFICATION OF CYTOCHROME-P450 ISOZYMES INVOLVED IN METABOLISM OF THE ALPHA(1)-ADRENOCEPTOR BLOCKER TAMSULOSIN IN HUMAN LIVER-MICROSOMES

1. The in vitro human liver metabolism of the alpha(1)-adrenaceptor bl ocker tamsulosin was investigated. When C-14-tamsulosin was incubated with human liver microsomes, it was converted to five known urinary me tabolites and at least three unknown metabolites. Of the former group, the predominant metabolite was the O-deethylated metabolite (M-1), fo llowed by the o-ethoxyphenoxy acetic acid (AM-1) and the m-hydroxylate d metabolite (M-3). 2. There was a good linear relationship between AM -1 formation and testosterone 6 beta-hydroxylase activity in microsome s from each of 10 individual donors. The rate of M-1 formation also co rrelated with the same activity, albeit the correlation curve did not pass through the origin. By contrast, the rates of M-3 and the O-demet hylated metabolite (M-4) formation correlated with dextromethorphan O- demethylase activity. 3. Ketoconazole strongly inhibited AM-I formatio n and reduced that of M-l by c. 60%. Immunoinhibition studies using an ti-rat antibodies supported these results. The formation of M-3 and M- 4 was inhibited by quinidine and sparteine. 4. It is concluded that fo rmation of tamsulosin metabolites, AM-I and M-1, is catalysed by CYP3A 4 whereas that of M-3 and M-4 is catalysed by CYP2D6. However, minor c ontributions from other CYPs cannot be excluded.