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.
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