A. Yokono et al., The effect of CYP2C19 and CYP2D6 genotypes on the metabolism of clomipramine in Japanese psychiatric patients, J CL PSYCH, 21(6), 2001, pp. 549-555
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.