Genetic Polymorphisms Contribute to the Individual Variations of Imatinib Mesylate Plasma Levels and Adverse Reactions in Chinese GIST Patients
作者单位：Department of Clinical Pharmacy School of Pharmacy Fudan University Department of Medical Oncology Shanghai Cancer Center Fudan University Department of Pathology Zhongshan Hospital Fudan University Department of General Surgery Zhongshan Hospital Fudan University Department of Medical Oncology Zhongshan Hospital Fudan University
会议名称：《石河子大学2017年“一带一路”核心区创新驱动发展博士...》
会议日期：2017年
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：supported by the Shanghai Municipal Commission of Health and Family Planning,key development discipline(No.2015ZB0201) the Shanghai Municipal Science and Technology Commission(13411950802 and 14411970000)
关 键 词：imatinib mesylate gastrointestinal stromal tumor genetic polymorphisms plasma levels adverse reactions Chinese
摘 要：Imatinib mesylate（IM） has dramatically improved the outcomes of gastrointestinal stromal tumor（GIST） patients. However, the clinical responses of IM may considerably vary among single individuals. This study aimed to investigate the influences of genetic polymorphisms of drug-metabolizing enzyme（CYP3A4）, transporters（ABCB1, ABCG2）, and nuclear receptor（Pregnane X Receptor（PXR, encoded by NR1I2）） on IM plasma levels and related adverse reactions in Chinese GIST patients. A total of 68 Chinese GIST patients who have received IM 300–600 mg/day were genotyped for six single nucleotide polymorphisms（SNPs）（CYP3A4 rs2242480;ABCB1 rs1045642;ABCG2 rs2231137;NRI12 rs3814055, rs6785049, rs2276706）, and the steady-state IM trough plasma concentrations were measured by a validated HPLC method. There were statistically significant variances in the steady-state IM trough plasma concentrations（from 272.22 to 4365.96 ng/m L）. Subjects of GG in rs2242480, T allele carriers in rs1045642 and CC in rs3814055 had significantly higher steady-state IM dose-adjusted trough plasma concentrations. Subjects of CC in rs3814055 had significantly higher incidence rate of edema. The genetic polymorphisms of rs2242480, rs1045642, rs3814055 were significantly associated with IM plasma levels, and the genetic variations of rs3814055 were significantly associated with the incidence rate of edema in Chinese GIST patients. The current results may serve as valuable fundamental knowledge for IM therapy in Chinese GIST patients.