文章基本信息

标题：Influence of Cytochrome P450 2C19 Gene Variations on Pharmacokinetic Parameters of Thalidomide in Japanese Patients
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作者：Naoki Matsuzawa ; Katsunori Nakamura ; Masayuki Matsuda 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2012
卷号：35
期号：3
页码：317-320
DOI：10.1248/bpb.35.317
出版社：The Pharmaceutical Society of Japan
摘要：Purpose: Cytochrome P450 ( CYP ) 2C19 polymorphisms may partly explain the variability of thalidomide concentration and adverse drug effects by altering its metabolism. To compare the genetic and clinical factors responsible for the adverse effects and efficacy of thalidomide treatment, we investigated CYP2C19 genetic polymorphisms in Japanese subjects. Materials and Methods: Variations in the CYP2C19 gene in 6 patients treated with thalidomide were analyzed. The dosage of thalidomide, concentrations of ( R )- and ( S )-thalidomide in whole blood, and clinical laboratory test results were used as pharmacokinetic and pharmacodynamic indices. Using genomic DNA, CYP2C19*2 and * 3 allele frequencies were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. Results: The frequencies of CYP2C19 PM and hetero EM (hetEM) genotypes in Japanese patients taking thalidomide were 2 (33.3%) and 4 (66.7%), respectively. The areas under the curve ( AUC ) of ( R )-thalidomide were 3.42 and 5.33 μg·h/L, and those of ( S )-thalidomide were 1.64 and 2.46 μg·h/L for hetEM and PM, respectively. Conclusions: This study provided new insights regarding the contribution of CYP2C19 gene variations to adverse responses to thalidomide. Genotyping of CYP2C19*2 and *3 can be considerably simplified by using KOD FX as a polymerase for prediction of adverse effects to thalidomide by the PCR-RFLP method. CYP2C19 PM patients tend to have high serum thalidomide concentrations.
关键词：thalidomide;cytochrome P450 2C19;polymorphism;multiple myeloma