Effects of 5‐HT_₃ receptor antagonists on cisplatin‐induced kidney injury

Abstract

Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin.Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin-induced kidney injury has been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5-HT 3 receptor antagonists used clinically for cisplatin-induced renal injury have not been elucidated. Therefore, the aim of this study was to investigate the effects of 5-HT 3 receptor antagonists in a mouse model of cisplatin-induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3,000 hospital medical records. The concomitant use of a first-generation 5-HT 3 receptor antagonist (ondansetron, granisetron, or ramosetron) significantly increased cisplatin accumulation in the kidney and worsened renal damage.Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of cisplatin alone. Furthermore, an analysis of data from the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that the combination treatment of cisplatin and a first-generation 5-HT 3 receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second-generation 5-HT 3 receptor antagonist. These results suggest that compared with the first-generation antagonists, second-generation 5-HT 3 receptor antagonists do not worsen cisplatin-induced acute kidney injury. The findings should be validated in a prospective controlled trial before implementation in clinical practice.

Concomitant palonosetron ameliorates cisplatin-induced nephrotoxicity, nausea, and vomiting: a retrospective cohort study and pharmacovigilance analysis

“…CDDP is mainly transported to renal tissues via organic cation transporter 2 (OCT2) at the renal basolateral membrane [ 12 , 13 ], whereas CDDP is excreted into urine through multidrug and toxin extrusion protein transporter 1 (MATE1), which is localized on the apical membrane [ 14 ], indicating that OCT2 and MATE1 should be responsible for CDDP-induced nephrotoxicity. As shown in a previous study using the mice model of CDDP-induced nephrotoxicity [ 8 ], the concomitant use of a first-generation 5-HT 3 RA (ondansetron, granisetron, or ramosetron) significantly increased CDDP accumulation in the kidneys and worsened renal damage. Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of CDDP alone.…”

“…Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of CDDP alone. An uptake study in hMATE1-expressing HEK293 cells revealed that the first-generation 5-HT 3 RAs have a lower IC 50 than palonosetron, thus, palonosetron is thought to have weaker MATE1 inhibitory activity than the first-generation 5-HT 3 RAs [ 8 ]. Furthermore, palonosetron was reported to interfere with OCT2 activity [ 15 ].…”

“…In the present study, there was no significant difference in the incidence of hematological toxicity between patients treated with palonosetron and ramosetron (Table 2 ). However, a previous study reported that combination treatment with palonosetron did not affect the blood levels of CDDP in mice [ 8 ]. Thus, it is likely that plasma concentration of CDDP is not affected by co-administration of palonosetron and/or ramosetron.…”

“…A previous retrospective study reported that palonosetron suppressed CDDP-induced increases in serum creatinine (Scr) and blood urea nitrogen (BUN) levels from clinical data treated with CDDP and 5-HT 3 RAs [ 7 ]. Furthermore, an analysis using the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that first-generation 5-HT 3 RAs (ondansetron, granisetron, or ramosetron) significantly increased renal adverse events associated with CDDP as compared with a second-generation 5-HT 3 RA, palonosetron [ 8 ]. However, the advantage of palonosetron on CDDP-induced nephrotoxicity and CINV in comparison with other 5-HT 3 RAs remains unclear in patients with the triple antiemetic therapy.…”

Drug-Repositioning Approaches Based on Medical and Life Science Databases

“…The first approach, similar to the first approach, is for cisplatin renal injury ( Goda et al, 2021 ). Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and a 5-HT3 receptor antagonist is used as an antiemetic.…”