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 imipra mine and its metabolites in plasma and urine simultaneously after a si ngle oral dose of 25 mg of imipramine hydrochloride administered to 16 healthy (three Japanese and 13 Korean volunteers. Four of the subject s were poor metabolizers (PMs) of metoprolol but extensive metabolizer s (EMs) of S-mephenytoin (PM(ML)/EM(MP)), five subjects were EMs of me toprolol but PMs of S-mephenytoin (EM(ML)/PM(MP)) and seven subjects w ere 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)/E M(MP) group and the EM(MP)/PM(MP) group than in the EM(ML)/EM(MP) grou p, 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 plasm a 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 s maller (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 rat io of desipramine/imipramine (P < .05) but negatively with the AUC rat io of desipramine/imipramine (P < .05). Log(10) percent 4'-hydroxymeph enytoin excreted in 8-hr urine correlated positively with the AUC of d esipramine (P < .01) and with the AUC ratio of despiramine/imipramine (P < .01). The urinary excretions of imipramine and its metabolites al so reflected the data derived from plasma samples in the three differe nt phenotype-paired panels. The results suggest that the 2-hydroxylati on and the N-demethylation of imipramine metabolism are under a pharma cogenetic control of debrisoquin- and S-mephenytoin-type oxidation, re spectively, in Oriental subjects.