Effects of genetic defects in the CYP2C19 gene on the N-demethylation of imipramine, and clinical outcome of imipramine therapy.
The relationship between the genetic polymorphism of S-mephenytoin 4'-hydroxylation catalyzed by CYP2C19 and the N-demethylation of imipramine was examined in 10 Japanese depressed patients. Five patients, who were poor metabolizers of S-mephenytoin, were determined to be either homozygous for a mutation in exon 5 or heterozygous for mutations in exon 4 and exon 5 of the CYP2C19 gene. In contrast, five patients, who were extensive metabolizers, had no mutations. The demethylation index (the desipramine/imipramine ratio) was significantly lower in patients with genetic defects. Plasma levels of imipramine and 2-hydroxyimipramine normalized by the daily dose (mg) per weight (kg) were significantly higher in patients with genetic defects. This suggests that the N-demethylation of imipramine is impaired in patients with genetic defects in the CYP2C19 gene, and that genotype determination may be useful in preventing side effects induced by unexpectedly elevated levels of imipramine.
Morinobu
S
S
Department of Neuropsychiatry, Yamagata University School of Medicine, Japan.
Tanaka
T
T
Kawakatsu
S
S
Totsuka
S
S
Koyama
E
E
Chiba
K
K
Ishizaki
T
T
Kubota
T
T
D000328:Adult; D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004252:DNA Mutational Analysis; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005091:Exons; D005260:Female; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D007099:Imipramine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D016896:Treatment Outcome
D000929:Antidepressive Agents, Tricyclic; C033803:2-hydroxyimipramine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D007099:Imipramine