Effects of nortriptyline on the activities of human and rat liver microsome bufuralol 1'-hydroxylase in vitro

The effects of nortriptyline in vitro on the activities of optical isomer and racemate bufuralol 1'-hydroxylase in man and Wistar rat liver microsomal fractions were studied. There was a dose-dependent inhibitory effect of nortriptyline on bufuralol 1'-hydroxylase in both species. While the concentration of nortriptyline greater than or equal to 0.32 mumol/L and greater than or equal to 1.6 mumol/L, the activities of (+), (-) and (+/-) bufuralol 1'-hydroxylase were significantly reduced in man and rat, respectively. The values of inhibitor concentration causing 50% reduction (IC50) to (+), (-) and (+/-) bufuralol 1'-hydroxylase were 10, 19 and 14 mumol/L for human and 4, 10, 6 mumol/L for rat, respectively. It was shown by improved Dixon's plot that the inhibitory type was competitive, and the inhibitory constant (Ki) values to (+), (-) and (+/-) bufuralol 1'-hydroxylase were 5, 3, 4 mumol/L for human and 55, 29, 43 mumol/L for rat, respectively. These results indicate that nortriptyline is a very potent competitive inhibitor to bufuralol 1'-hydroxylase in man and Wistar rat.