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 (PMML/EMMP), five subjects were EMs of metoprolol but PMs of S-mephenytoin (EMML/PMMP) and seven subjects were EMs of both metoprolol and S-mephenytoin (EMML/EMMP). The mean (+/- S.D.) oral clearances of imipramine were smaller in the PMML/EMMP group and the EMML/PMMP group than in the EMML/EMMP group, although a statistical difference (P < .05) was found only in the EMML/PMMP vs. the EMML/EMMP group. The mean area under the plasma concentration-time curve (AUC) of desipramine was 9 times greater (P < .01) in PMML/EMMP group, whereas the mean value was 0.6 times smaller (P < .05) in the EMML/PMMP group than in the EMML/EMMP group. The log10 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 2-hydroxyimipramine/imipramine (P < .05). Log10 percent 4'-hydroxymephenytoin excreted in 8-hr urine correlated positively with the AUC of desipramine (P < .01) and with the AUC ratio of desipramine/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.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Clinical Pharmacology, International Medical Center of Japan, Tokyo.
E
E
Koyama
D R
DR
Sohn
S G
SG
Shin
K
K
Chiba
J G
JG
Shin
Y H
YH
Kim
H
H
Echizen
T
T
Ishizaki
D000328:Adult; D044466:Asian People; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D003640:Dealkylation; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007099:Imipramine / Q000493:pharmacokinetics*; D007527:Isoenzymes / Q000502:physiology*; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D008790:Metoprolol / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000502:physiology*; D010641:Phenotype
D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol; D007099:Imipramine; D008617:Mephenytoin