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 (OCT2) 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 OCT2 (SLC22A2) with the disposition of cisplatin. Experimental Design: Cell lines were transfected using the Flp-In 293 system with the fulllength 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 tetraethylammonium was significantly increased (P < 0.0001) in OCT2-transfected cells compared with empty vector-transfected controls. OCT2-mediated transport of cisplatin was saturable, and uptake was increased by f4-fold (P < 0.0001) relative to control cells. Cisplatin inhibited OCT2-mediated transport of tetraethylammonium by up to 97 %. The mean F SD systemic clearance of unbound cisplatin-derived platinum in the patient population was 29.2 F 8.39 L/h, and renal clearance was particularly variable. Only one single nucleotide polymorphism (Ala 270 Se; rs316019) was identified (minor allele frequency,7.6%), andit 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.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…The antineoplastic drug cisplatin is both a substrate and inhibitor of OCT2 activity (Ciarimboli et al, 2005b;Yokoo et al, 2007;Filipski et al, 2008). Cisplatin accumulation and cytotoxicity are enhanced by overexpression of rat and human OCT2 and, to a lesser degree, OCT1 Yokoo et al, 2007).…”

“…Compared with wild-type mice, Oct1/2-null mice have reduced platinum excretion and are protected from cisplatin nephrotoxicity (Filipski et al, 2009). Likewise, the A270S SLC22A2 variant was associated with protection against renal damage in a small cohort of white patients receiving cisplatin-containing chemotherapy regimens (Table 13) (Filipski et al, 2008(Filipski et al, , 2009). Coadministration of the anticancer drug imatinib prevents renal accumulation and toxicity of cisplatin, probably by interfering with OCT2-mediated transport (Tanihara et al, 2009).…”

Assessment of Vandetanib as an Inhibitor of Various Human Renal Transporters: Inhibition of Multidrug and Toxin Extrusion as a Possible Mechanism Leading to Decreased Cisplatin and Creatinine Clearance

“…Human organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), and MATE2K are highly expressed in the brush-border membrane of the kidneys (proximal tubule epithelial cells) and are thought to play a role in the clearance of cisplatin (Ciarimboli et al, 2010;Ciarimboli, 2011;Liu et al, 2012;Sprowl et al, 2013). In agreement, the recovery of a cisplatin dose in urine is markedly reduced in mice deficient in both OCT1 and OCT2 (Filipski et al, 2008). Similarly, inhibition by cimetidine and gene deletion decreases OCT2-mediated renal uptake of cisplatin and ameliorates nephrotoxicity (Franke et al, 2010).…”

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

“…These three structural motifs previously were found to be overrepresented in potent inhibitors of the organic cation transporter OCT2 (53)(54)(55). The presence of these motifs is of potential interest because OCT2 is responsible for accumulation of cisplatin in renal cells (35,37,56). In mice, two closely related organic , and renal tissues isolated on day 3 were used for microarray analysis of select genes, including CDK4 and CDK6.…”