Pharmacologie clinique et biopharmaceutique

Abstrait

Influence of Renal ABC and SLC Transporter Polymorphisms on Cisplatin-induced Nephrotoxicity in Patients with Esophageal Cancer

Kazuma Fujita, Takenori Niioka*, Satoru Motoyama and Masatomo Miura

Background: The individual and collective contributions of genetic polymorphisms in drug transporter genes in human renal proximal tubules to cisplatin-induced nephrotoxicity are still unclear. Methods: In this study, we investigated the effects of polymorphisms in SLC22A2 (808G>T), SLC31A1 (rs10981694A>C, rs12686377G>T, rs7851395A>G), SLC47A1 (rs2289669G>A), ABCB1 (1236C>A, 2677G>T/A, 3435C>T), ABCC2 (-24C>T), and ABCG2 (421C>A) on cisplatin-induced nephrotoxicity in 131 patients with esophageal cancer receiving 5-fluorouracil and cisplatin (FP) chemotherapy. The change rate of the estimated glomerular filtration rate (eGFR) was calculated according to the following formula: eGFR before FP chemotherapy-lowest eGFR during first cycle after FP chemotherapy)/eGFR before FP chemotherapy. Results: In univariate analysis, there was a significant correlation between patient age and the change rate of the eGFR by cisplatin (P = 0.021). However, there were no significant differences in the change rate of the eGFR by cisplatin between SLC22A2, SLC47A1, SLC31A1, ABCB1, ABCC2, and ABCG2 polymorphisms. Multivariate analysis revealed that only age was an independent variable predicting a higher risk of cisplatin-induced acute renal dysfunction. Conclusion: In FP chemotherapy for esophageal cancer patients, cisplatin-induced nephrotoxicity was not affected by polymorphisms in the uptake transporters OCT2 and Ctr1 or efflux transporters MATE1, P-glycoprotein, MRP2, and BCRP. Since degradation of renal function due to aging reduces cisplatin clearance, the cisplatin dosage should be carefully chosen in elderly patients.