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 by )) 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) (; ; ; , , ), 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 in , allele carriers in and in had significantly higher steady-state IM dose-adjusted trough plasma concentrations. Subjects of in had significantly higher incidence rate of edema. The genetic polymorphisms of , , were significantly associated with IM plasma levels, and the genetic variations of 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.