Evaluation of the association of SNP in carboxylesterase enzyme with pharmacokinetic and adverse effects of capecitabine in breast and colorectal cancer patients

Capecitabine is tumor-selective fluoropyrimidine carbamate, an oral prodrug of 5-fluorouracil (5-FU), approved for treatment of breast, colorectal and gastric cancer. Interindividual differences in drug-metabolizing enzymes' activity may affect efficacy and toxicity, especially among anticancer agents. The aim of this study to evaluate the association of SNP in CES1, involved in the metabolism of 5-FU, with pharmacokinetic and adverse effects of capecitabine. Plasma samples were obtained from 7 breast and colorectal cancer patients who treated with capecitabine-based chemotherapy (1000-1250 mg/m2) at 0.5, 1, 2, 3, 4 hour following drug administration in first day of first cycle. Plasma concentrations of capecitabine were determined by using HPLC. SNP (rs8192950) was genotyped by using the RT-PCR in DNA samples and observed side effects was examined by doctor in the end of first cycle. Patients were found as heterozygote (57%), wild (29%), mutant (14%) distributions of genotypes (p=0.909). Analysis of the plasma samples showed that average AUC0-4sa 4.60±2.25 µg.h/ml, Cmax 3.19±2.5 µg/ml. No statistically significant differences between genotypes and AUC values (p=0.7059) and the most frequently observed side effects which are diarrhea (p=0.1028), asthenia (p=0.6456), anemia (p=0.6456), emesis (p=0.3499) were observed. This is the first study evaluating an association of genetic variation in CES1 (rs8192950) with pharmacokinetic and adverse effects of capecitabine. Therefore, additional study in larger groups of patients is required to support our study. Our study will offer an insight into the pharmacogenetic researches to personalized chemotherapy and will provide basic knowledge to related studies. Key Words: Capecitabine, carboxylesterase, pharmacogenetic, breast cancer, colorectal cancer