INHIBITORS OF IMIPRAMINE METABOLISM BY HUMAN LIVER-MICROSOMES

1 The aromatic 2-hydroxylation of imipramine was studied in microsomes from three human livers. The kinetics were best described by a biphasic enzyme model. The estimated values of V(max) and K(m) for the high affinity site ranged from 3.2 to 5.7 nmol mg-1 h-1 and from 25 to 31-mu-M, respectively. 2 Quinidine was a potent inhibitor of the high affinity site for the 2-hydroxylation of imipramine in microsomes from all three human livers, with apparent K(i)-values ranging from 9 to 92 nM. This finding strongly suggests that the high affinity enzyme is CYP2D6, the source of the sparteine/debrisoquine oxidation polymorphism. 3 The selective serotonin reuptake inhibitors (SSRI), paroxetine, fluoxetine and norfluoxetine were potent inhibitors of the high affinity site having apparent K(i)-values of 0.36, 0.92 and 0.33-mu-M, respectively. Three other SSRIs, citalopram, desmethyl-citalopram and fluvoxamine, were less potent inhibitors of CYP2D6, with apparent K(i)-values of 19, 1.3 and 3.9-mu-M, respectively. 4 Among 20 drugs screened. fluvoxamine was the only potent inhibitor of the N-demethylation of imipramine. with a K(i)-value of 0.14-mu-M. 5 Neither mephenytoin, citalopram, diazepam, omeprazole or proguanil showed any inhibition of the N-demethylation of imipramine and the role of the S-mephenytoin hydroxylase for this oxidative pathway could not be confirmed.