Kosaki Kenjiro, Tamura Kazuyo, Sato Reiko, Samejima Hazuki, Tanigawara Yusuke, Takahashi Takao
Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Brain Dev. 2004 Dec;26(8):530-4. doi: 10.1016/j.braindev.2004.02.010.
N-desmethylclobazam (N-CLB), the major metabolite of clobazam (CLB), exerts a large influence on therapeutic and adverse effects of CLB. A substantial inter-individual variability has been observed in the ratios of N-CLB concentration/CLB dose and of the N-CLB/CLB concentration. We document here a genotype-phenotype correlation between CYP2C19 polymorphisms and those ratios. Patients with two mutated CYP2C19 alleles show significantly higher ratios than those with the wild type genotype: patients with one mutated allele exhibited intermediate trait. That is, the degree of elevation in the ratios was dependent on the number of mutated alleles of CYP2C19 (gene-dose effect). The N-CLB concentration/CLB dose ratio of patients with two mutated alleles was more than six fold higher than that of wild type patients. Thus, the serum N-CLB/CLB concentration ratio may be a valuable parameter to screen for patients at risk for side effects. Such precautions may be clinically relevant in populations where the mutant allele frequency is high, such as in Asian populations ( approximately 35%). Patients co-medicated with CYP3A4 inducer showed lower CLB concentration/CLB dose ratios and higher N-CLB/CLB concentration ratios. The overall effect of CYP3A4 inducer on N-CLB metabolism, however, was small and, thus, we conclude that the CYP2C19 genotype is the major determinant of the N-CLB concentration. For this reason it is crucial for the better management of epilepsy and other chronic illnesses in general to establish the correlation of genotype of CYP enzymes and pharmacokinetics/dynamics of drugs.
N-去甲基氯巴占（N-CLB）是氯巴占（CLB）的主要代谢产物，对CLB的治疗效果和不良反应有很大影响。在N-CLB浓度/CLB剂量比以及N-CLB/CLB浓度比方面，个体间存在很大差异。我们在此记录了CYP2C19基因多态性与这些比值之间的基因型-表型相关性。携带两个CYP2C19突变等位基因的患者的比值显著高于野生型基因型患者：携带一个突变等位基因的患者表现出中等性状。也就是说，比值升高的程度取决于CYP2C19突变等位基因的数量（基因剂量效应）。携带两个突变等位基因的患者的N-CLB浓度/CLB剂量比是野生型患者的六倍多。因此，血清N-CLB/CLB浓度比可能是筛选有副作用风险患者的一个有价值的参数。在突变等位基因频率较高的人群中，如亚洲人群（约35%），这种预防措施可能具有临床相关性。同时服用CYP3A4诱导剂的患者的CLB浓度/CLB剂量比更低，N-CLB/CLB浓度比更高。然而，CYP3A4诱导剂对N-CLB代谢的总体影响较小，因此，我们得出结论，CYP2C19基因型是N-CLB浓度的主要决定因素。出于这个原因，一般来说，为了更好地管理癫痫和其他慢性疾病，建立CYP酶基因型与药物药代动力学/药效学之间的相关性至关重要。
