A major influence of CYP2C19 genotype on the steady-state concentration of N-desmethylclobazam
A major influence of CYP2C19 genotype on the steady-state concentration of N-desmethylclobazam
复制标题
DOI：
10.1016/j.braindev.2004.02.010
复制
发表时间：
2004-12-01
影响因子：
1.7
通讯作者：
Takahashi, T
中科院分区：
文献类型：
--
作者：
Kosaki, K;Tamura, K;Takahashi, T
氯巴坦的主要代谢产物N-去甲基氯巴坦(N-CLB)对CLB的疗效和不良反应有很大影响。在N-CLB浓度/CLB剂量和N-CLB/CLB浓度的比率中观察到了很大的个体间变异性。我们在这里记录了CYP2C19基因多态和这些比率之间的基因-表型相关性。携带两个突变等位基因的患者表现出明显高于野生型的比例：携带一个突变等位基因的患者表现出中间性状。也就是说，这些比率的升高程度取决于CYP2C19突变等位基因的数量(基因剂量效应)。两个突变等位基因患者的N-CLB浓度/M剂量比是野生型患者的6倍以上。因此，血清N-CLB/CLB浓度比值可能是筛选有副作用风险患者的一项有价值的参数。这样的预防措施可能在突变等位基因频率较高的人群中具有临床意义，例如在亚洲人群中(类似于35%)。联合使用CYP3A4诱导剂的患者，其CLB浓度/CLB剂量比较低，N-CLB/CLB浓度比较高。然而，CYP3A4诱导剂对N-CLB代谢的总体影响很小，因此，我们得出结论，CYP2C19基因是N-CLB浓度的主要决定因素。因此，为了更好地治疗癫痫和其他慢性疾病，建立CYP酶基因与药物的药代动力学/动力学的相关性是至关重要的。(C)2004爱思唯尔B.V.保留所有权利。
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/M 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 (similar to35%). 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. (C) 2004 Elsevier B.V. All rights reserved.