Interaction of cisplatin with the human organic cation transporter 2

Abstract

Purpose: Cisplatin is predominantly eliminated in the urine through active secretion. As the solute carrier organic cation transporter 2 (0CT2) is highly expressed in the basolateral membrane of proximal tubules, we determined its contribution to cisplatin transport and assessed the relation of variation in the gene encoding 0CT2 (SLC22A2) with the disposition of cisplatin. Experimental Design: Cell lines were transfected using the Flp-ln 293 system with the full- length OCT2 cDNA, and platinum concentrations were measured using flameless atomic absorption spectrometry. Pharmacokinetic data were available from 106 cancer patients, and DNA was screened for eight nonsynonymous SLC22A2 variants using direct sequencing. Results: mRNA expression was 36-fold higher and uptake of the model substrate tetraethylam- monium was significantly increased (P > 0.0001) in OCT2-transfected cells compared with empty vector-transfected controls. 0CT2-mediated transport of cisplatin was saturable, and uptake was increased by ∼ 4-fold (P > 0.0001) relative to control cells. Cisplatin inhibited 0CT2-mediated transport of tetraethylammonium by up to 97%. The mean ± SD systemic clearance of unbound cisplatin-derived platinum in the patient population was 29.2 ± 8.39 L/h, and renal clearance was particularly variable. Only one single nucleotide polymorphism (Ala 270Se; rs316019) was identified (minor allele frequency, 7.6 %), and it was not found to be associated with any of the studied pharmacokinetic variables (P < 0.05). Conclusion:These findings support the hypothesis that OCT2 is a key renal transporter involved in cisplatin elimination. However, known variants in SLC22A2 do not substantially contribute to explaining interindividual pharmacokinetic variability, suggesting that other mechanisms, controlling OCT2 expression, might be involved. © 2008 American Association for Cancer Research.