title: The effect of CYP2C19 and CYP2D6 genotypes on the metabolism of clomipramine in Japanese psychiatric patients.
abstract: In this study, the authors investigated the relationship between the metabolism of clomipramine (C) and the genotypes of cytochrome P450 (CYP) CYP2C19 and CYP2D6. Fifty-one Japanese patients (18 men and 33 women) were administered 10 to 250 mg/day of C by mouth and maintained on the same daily dose of C for at least 2 weeks to obtain steady-state concentrations. Plasma levels of C and its metabolites N-desmethylclomipramine (DC), 8-hydroxyclomipramine, and 8-hydroxy-N-desmethylclomipramine (HDC) were determined by high-performance liquid chromatography. The allele frequencies of CYP2C19*2, CYP2C19*3, CYP2D6*5, and CYP2D6*10 were 27.5%, 12.8%, 2.9%, and 43.1%, respectively. Subjects who were homozygous for mutated alleles of CYP2C19 showed approximately 75% higher concentrations of C corrected by dose and body weight compared with those who were homozygous for wild-type alleles. Also, subjects who were homozygous for mutated alleles of CYP2C19 showed an approximately 68% higher value of C/DC compared with those who were homozygous for wild-type alleles. No significant difference in the ratio of DC/HDC was observed between subjects who were homozygous for mutated alleles of CYP2D6 and those who were homozygous for wild-type alleles. These results suggest that genotyping CYP2C19 is useful for grossly predicting the risk of getting high plasma concentrations of C and the low individual capacity to demethylate C because there is marked interindividual variability within each genotype. However, the genotyping of CYP2D6 is not useful for predicting the individual capacity to hydroxylate DC.
authors.affiliation: Department of Psychiatry, Shiga University of Medical Science, Otsu, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yokono
authors.forename: S
authors.initials: S
authors.lastname: Morita
authors.forename: T
authors.initials: T
authors.lastname: Someya
authors.forename: G
authors.initials: G
authors.lastname: Hirokane
authors.forename: M
authors.initials: M
authors.lastname: Okawa
authors.forename: K
authors.initials: K
authors.lastname: Shimoda
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000483:Alleles; D000929:Antidepressive Agents, Tricyclic / Q000097:blood / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D002997:Clomipramine / Q000097:blood / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D003866:Depressive Disorder / Q000097:blood / Q000201:enzymology / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010361:Patients / Q000706:statistics & numerical data; D012044:Regression Analysis; D012737:Sex Factors
chemical_list: D000929:Antidepressive Agents, Tricyclic; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D002997:Clomipramine