Genetic Polymorphisms Contribute to the Individual Variations of Imatinib Mesylate Plasma Levels and Adverse Reactions in Chinese GIST Patients.
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 byNR1I2)) 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/mL). Subjects ofGGinrs2242480,Tallele carriers inrs1045642andCCinrs3814055had significantly higher steady-state IM dose-adjusted trough plasma concentrations. Subjects ofCCinrs3814055had significantly higher incidence rate of edema. The genetic polymorphisms ofrs2242480,rs1045642,rs3814055were significantly associated with IM plasma levels, and the genetic variations ofrs3814055were 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.
Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai 201203, China. nihaoliujing_001@126.com.
Jing
J
Liu
Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China. chanhj75@aliyun.com.
Zhiyu
Z
Chen
Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai 201203, China. 14211030047@fudan.edu.cn.
Hanmei
H
Chen
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. hou.yingyong@zs-hospital.sh.cn.
Yingyong
Y
Hou
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. lu.weiqi@zs-hospital.sh.cn.
Weiqi
W
Lu
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. doctorhjy@163.com.
Junyi
J
He
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. thx121@163.com.
Hanxing
H
Tong
Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. zhou.yuhong@zs-hospital.sh.cn.
Yuhong
Y
Zhou
Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai 201203, China. weimincai@fudan.edu.cn.
Weimin
W
Cai
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D044466:Asian People; D015415:Biomarkers; D002681:China; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000970:Antineoplastic Agents; D015415:Biomarkers; D018160:Receptors, Cytoplasmic and Nuclear; D000068877:Imatinib Mesylate; D051544:Cytochrome P-450 CYP3A
Chinese; adverse reactions; gastrointestinal stromal tumor; genetic polymorphisms; imatinib mesylate; plasma levels