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Int. J. Mol. Sci. 2017, 18(3), 603; doi:10.3390/ijms18030603

Genetic Polymorphisms Contribute to the Individual Variations of Imatinib Mesylate Plasma Levels and Adverse Reactions in Chinese GIST Patients

1
Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai 201203, China
2
Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China
3
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
4
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
5
Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 31 December 2016 / Revised: 27 February 2017 / Accepted: 4 March 2017 / Published: 13 March 2017
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Abstract

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/mL). 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. View Full-Text
Keywords: imatinib mesylate; gastrointestinal stromal tumor; genetic polymorphisms; plasma levels; adverse reactions; Chinese imatinib mesylate; gastrointestinal stromal tumor; genetic polymorphisms; plasma levels; adverse reactions; Chinese
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MDPI and ACS Style

Liu, J.; Chen, Z.; Chen, H.; Hou, Y.; Lu, W.; He, J.; Tong, H.; Zhou, Y.; Cai, W. Genetic Polymorphisms Contribute to the Individual Variations of Imatinib Mesylate Plasma Levels and Adverse Reactions in Chinese GIST Patients. Int. J. Mol. Sci. 2017, 18, 603.

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