METABOLIC DISPOSITION OF IMIPRAMINE IN ORIENTAL SUBJECTS - RELATION TO METOPROLOL ALPHA-HYDROXYLATION AND S-MEPHENYTOIN 4'-HYDROXYLATION PHENOTYPES

We studied the metabolic disposition of imipramine by measuring imipramine and its metabolites in plasma and urine simultaneously after a single oral dose of 25 mg of imipramine hydrochloride administered to 16 healthy (three Japanese and 13 Korean volunteers. Four of the subjects were poor metabolizers (PMs) of metoprolol but extensive metabolizers (EMs) of S-mephenytoin (PM(ML)/EM(MP)), five subjects were EMs of metoprolol but PMs of S-mephenytoin (EM(ML)/PM(MP)) and seven subjects were EMs of both metoprolol and S-mephenytoin (EM(ML)/EM(MP)). The mean (+/- S.D.) oral clearances of imipramine were smaller in the PM(ML)/EM(MP) group and the EM(MP)/PM(MP) group than in the EM(ML)/EM(MP) group, although a statistical difference (P < .05) was found only in th EM(ML)/PM(MP) vs. the EM(ML)/EM(MP) group. The mean area under the plasma concentration-time curve (AUC) of desipramine was 9 times greater (p < .01) in PM(ML)/EM(MP) group, whereas the mean value was 0.6 times smaller (P < .05) in the EM(ML)/PM(MP) group than in the EM(ML)/EM(MP) group. The log(10) metoprolol/alpha-hydroxymetoprolol ratio correlated positively with the AUC of desipramine (P < .01) and with the AUC ratio of desipramine/imipramine (P < .05) but negatively with the AUC ratio of desipramine/imipramine (P < .05). Log(10) percent 4'-hydroxymephenytoin excreted in 8-hr urine correlated positively with the AUC of desipramine (P < .01) and with the AUC ratio of despiramine/imipramine (P < .01). The urinary excretions of imipramine and its metabolites also reflected the data derived from plasma samples in the three different phenotype-paired panels. The results suggest that the 2-hydroxylation and the N-demethylation of imipramine metabolism are under a pharmacogenetic control of debrisoquin- and S-mephenytoin-type oxidation, respectively, in Oriental subjects.