Effects of genetic defects in the CYP2C19 gene on the N‐demethylation of imipramine, and clinical outcome of imipramine therapy

• Published in: Psychiatry and clinical neurosciences 1997-08, Vol.51 (4), p.253-257
• Main Authors: MORINOBU, SHIGERU, TANAKA, TAKESHI, KAWAKATSU, SHINOBU, TOTSUKA, SHIRO, KOYAMA, ERIKO, CHIBA, KAN, ISHIZAKI, TAKASHI, KUBOTA, TAKAHIRO
• Format: Article
• Language: English
• Subjects: Adult; Antidepressive Agents, Tricyclic - adverse effects; Antidepressive Agents, Tricyclic - pharmacokinetics; Antidepressive Agents, Tricyclic - therapeutic use; Aryl Hydrocarbon Hydroxylases; Biological and medical sciences; CYP2C19; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme System - genetics; depression; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - enzymology; Depressive Disorder, Major - genetics; DNA Mutational Analysis; Dose-Response Relationship, Drug; Exons; Female; Genetic Carrier Screening; Genotype; Humans; imipramine; Imipramine - adverse effects; Imipramine - analogs & derivatives; Imipramine - blood; Imipramine - pharmacokinetics; Imipramine - therapeutic use; Male; Medical sciences; Middle Aged; Mixed Function Oxygenases - genetics; Neuropharmacology; N‐demethylation; Pharmacology. Drug treatments; Polymorphism, Genetic - genetics; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; S‐mephenytoin; Treatment Outcome
• ISSN: 1323-1316; 1440-1819
• DOI: 10.1111/j.1440-1819.1997.tb02593.x

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.