Yokono A, Morita S, Someya T, Hirokane G, Okawa M, Shimoda K
Department of Psychiatry, Shiga University of Medical Science, Otsu, Japan.
J Clin Psychopharmacol. 2001 Dec;21(6):549-55. doi: 10.1097/00004714-200112000-00002.
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 CYP2C192, CYP2C193, CYP2D65, and CYP2D610 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.
在本研究中，作者调查了氯米帕明（C）的代谢与细胞色素P450（CYP）CYP2C19和CYP2D6基因型之间的关系。51名日本患者（18名男性和33名女性）口服给予10至250毫克/天的C，并以相同的每日剂量维持至少2周以达到稳态浓度。通过高效液相色谱法测定C及其代谢物N-去甲基氯米帕明（DC）、8-羟基氯米帕明和8-羟基-N-去甲基氯米帕明（HDC）的血浆水平。CYP2C192、CYP2C193、CYP2D65和CYP2D610的等位基因频率分别为27.5%、12.8%、2.9%和43.1%。与野生型等位基因纯合子相比，CYP2C19突变等位基因纯合子的受试者经剂量和体重校正后的C浓度高出约75%。此外，与野生型等位基因纯合子相比，CYP2C19突变等位基因纯合子的受试者的C/DC值高出约68%。在CYP2D6突变等位基因纯合子和野生型等位基因纯合子的受试者之间，未观察到DC/HDC比值的显著差异。这些结果表明，对CYP2C19进行基因分型有助于大致预测血浆中C浓度升高的风险以及个体对C去甲基化能力较低的情况，因为每种基因型内存在明显的个体差异。然而，对CYP2D6进行基因分型对于预测个体对DC羟基化的能力并无帮助。
