Association between genetic polymorphisms and variation of imatinib pharmacokinetics in gastrointestinal stromal tumors

Abstract

To investigate the influence of metabolic enzymes polymorphisms on variations of imatinib (IM) pharmacokinetics in gastrointestinal stromal tumors (GIST) patients. Clinical data of 118 Chinese GIST patients receiving 400 mg/d IM at Sun Yat-sen University Cancer Center between 2014 and 2016 were retrospectively analyzed. The plasma concentration of imatinib mesylate(IM) and its main metabolic N-demethyl imatinib (NDI) were determined by LC-MS/MS. CYP3A4 rs2242480, CYP1A2 rs762551, CYP2C19 rs28399505 and NR1I2 rs3814057 were genotyped by MassArray system. Association between drug concentration and polymorphism was examined by Whitney U test. P≤0.05 indicated close association and 0.05<P<0.10 indicated marginal association. Among 118 GIST patients, 63 were male and 55 were female with a median age of 55 (44 to 63) years. Primary lesion location was the stomach in 87 cases, intestine in 13 cases and other sites in 18 cases. All the patients received standard 400 mg/d IM. Concentration of IM (CIM) was (1 501.1±646.8) μg/L and concentration of NDI (CNDI) was (221.7±92.5) μg/L. Association analysis showed that CYP2C19 rs28399505 was closely associated with concentration of IM and NDI(P=0.002 and 0.028). The concentration of IM and NDI in patients with TC heterozygote was significantly lower than those with wildtype TT [CIM: (695.4±202.9) μg/L vs. (1 518.9±716.8) μg/L, P=0.002; CNDI:(133.3±59.8) μg/L vs. (244.5±99.1) μg/L, P=0.028]. NR1I2 rs3814057 was marginally associated with concentration of IM and NDI(CIM:P=0.079; CNDI:P=0.082), while CYP3A4 rs2242480 and CYP1A2 rs762551 were not associated with concentration of IM or NDI(all P>0.10). CYP2C19 may play an important role in IM metabolism. Detection of CYP2C19 polymorphism may be beneficial to clinical monitoring of IM and decision making of individualized treatment.