The effect of CYP2C19 and CYP2D6 genotypes on the metabolism of clomipramine in Japanese psychiatric patients

In this study, the authors investigated the relationship between the metabo lism of clomipramine (C) and the genotypes of cytochrome P450 (CYP) CYP2C19 and CYP2D6. Fifty-one Japanese patients (18 men and 33 women) were adminis tered 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 lev els of C and its metabolites N-desmethylclomipramine (DC), 8-hydroxyclomipr amine, and 8-hydroxy-N-desmethylclomipramine (HDC) were determined by high- performance liquid chromatography. The allele frequencies of CYP2C19*2, CYP 2C19*3, CYP2D6*5, and CYP2D6*10 were 27.5%, 12.8%, 2.9%, and 43.1%, respect ively. Subjects who were homozygous for mutated alleles of CYP2C19 showed a pproximately 75% higher concentrations of C corrected by dose and body weig ht compared with those who were homozygous for wild-type alleles. Also, sub jects who were homozygous for mutated alleles of CYP2C19 showed an approxim ately 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 obs erved between subjects who were homozygous for mutated alleles of CYP2D6 an d those who were homozygous for wild-type alleles. These results suggest th at genotyping CYP2C19 is useful for grossly predicting the risk of getting high plasma concentrations of C and the low individual capacity to demethyl ate C because there is marked interindividual variability within each genot ype. However, the genotyping of CYP2D6 is not useful for predicting the ind ividual capacity to hydroxylate DC.