Inhibition of desmethylimipramine 2-hydroxylation by drugs in human liver microsomes.

摘要: Abstract The 2-hydroxylation of desmethylimipramine (DMI) correlates strongly with the 4-hydroxylation debrisoquine (D) both in human volunteers and vitro comparing liver microsomes from different individuals. D competitively inhibits DMI suggesting that is hydroxylated by ‘debrisoquine hydroxylase’ which under monogenic control man. We have characterized effect drugs on hydroxylation measuring formation 2-OH-DMI HPLC using fluorescence detection. Amitriptyline, nortriptyline metoprolol inhibited indicating interaction catalytical site for 2-hydroxylation. Antipyrine amylobarbitone at concentrations similar to their Km-values metabolism did not inhibit DMI-hydroxylation. Thus, these compounds there was a good correspondence between drugs' capacity apparent vivo Thioridazine, chlorpromazine, quinidine quinine also DMI-hydroxylation competitively. Thioridazine an unusually potent inhibitor (apparent inhibition constant Ki=0.75 μM). Quinidine (Ki=0.27 μM) much more efficient than its isomer (Ki=12 Theophylline could but atypical kinetics. suggest this simple test as well earlier described tests debrisoquine, sparteine bufuralol can be used screen if interact liver.