Mirtazapine identified as a preventive agent against cisplatin-induced nephrotoxicity: Integrating in silico, in vitro, and in vivo analyses.

Cisplatin (CDDP), a platinum-based chemotherapeutic agent, is highly effective in the treatment of various solid tumors. However, CDDP-induced nephrotoxicity (CIN) remains a critical dose-limiting toxicity that compromises CDDP's therapeutic efficacy in clinical practice. Since renal accumulation of CDDP, which is mediated by organic cation transporter 2 (OCT2/SLC22A2), contributes to the onset of CIN, OCT2 inhibitors may serve as prophylactic agents for CIN. In the present study, we aimed to identify potential preventive agents against CIN using a novel drug repositioning strategy that integrates quantitative structure-activity relationship-based screening for hOCT2 inhibitors with a Food and Drug Administration Adverse Event Reporting System analysis for CIN, and to evaluate their renoprotective effects through in vitro and in vivo experiments. Based on our in silico integrated analysis, seven compounds were selected as promising candidates for the prevention of CIN. An in vitro uptake study in hOCT2-expressing human embryonic kidney 293 cells comparing the seven compounds demonstrated that mirtazapine exhibited the highest inhibitory activity against hOCT2. In a CIN mouse model, concomitant administration of mirtazapine markedly attenuated the CDDP-induced increases in blood urea nitrogen and serum creatinine levels, mRNA expression of tubular injury markers, and histological renal damage in a dose-dependent manner. Furthermore, renal accumulation of CDDP was significantly reduced following co-administration of mirtazapine in mice. These findings demonstrate that the concomitant use of mirtazapine ameliorates CIN through the inhibition of OCT2-mediated accumulation of CDDP in the mouse kidney. Our study provides crucial information for the establishment of novel protective approaches to minimizing CIN.