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Effects of genetic defects in the CYP2C19 gene on the N‐demethylation of imipramine, and clinical outcome of imipramine therapy
Author(s) -
MORINOBU SHIGERU,
TANAKA TAKESHI,
KAWAKATSU SHINOBU,
TOTSUKA SHIRO,
KOYAMA ERIKO,
CHIBA KAN,
ISHIZAKI TAKASHI,
KUBOTA TAKAHIRO
Publication year - 1997
Publication title -
psychiatry and clinical neurosciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.609
H-Index - 74
eISSN - 1440-1819
pISSN - 1323-1316
DOI - 10.1111/j.1440-1819.1997.tb02593.x
Subject(s) - imipramine , mephenytoin , demethylation , pharmacogenetics , exon , pharmacology , cyp2c19 , genotype , medicine , endocrinology , chemistry , genetics , biology , gene , gene expression , pathology , alternative medicine , dna methylation
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.