Comparison of cisplatin-induced nephrotoxicity between single-dose and split-dose administration to rats

• Published in: Biomedicine & pharmacotherapy 2022-03, Vol.147, p.112619-112619, Article 112619
• Main Authors: Fukushima, Keizo, Futatsugi, Azusa, Maekawa, Maiko, Naito, Saya, Okada, Akira, Sugioka, Nobuyuki
• Format: Article
• Language: English
• Subjects: Acute kidney injury; Chronic kidney disease; Cisplatin; Fractionated administration; Hydration; Split dose
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.112619

To prevent cisplatin (CDDP)-induced nephrotoxicity, co-treatment with massive hydration is essential for its clinical use. However, some patients are ineligible for this treatment. For such patients, a split dose of CDDP has been suggested as an alternative strategy. This study aimed to evaluate the nephrotoxicity of a split dose of CDDP by direct comparison with the conventional single dose of CDDP in rats. Rats were allocated to single- or split-dose groups. In the single-dose group, rats received the total dose of CDDP (from 0 to 7.5 mg/kg) with a single injection, whereas the same total dose of CDDP was split equally across five doses in the corresponding split-dose group. Blood samples were taken until day 21 after the first CDDP injection to monitor the plasma creatinine (Cr) concentration as an index of nephrotoxicity. CDDP-induced nephrotoxicities from day 1–10 and from day 15–21 were defined as acute kidney injury (AKI) and subchronic kidney injury (sCKI), respectively. The toxicity of CDDP-induced AKI in the split-dose group was found to be significantly lower than that in the single-dose group at any given total dose level. At a total dose of 7.5 mg/kg, a decrease of approximately 90% in AKI was found in the split-dose group, while the extent of attenuation of CDDP-induced sCKI in this group was approximately 30%. Our results provide evidence that a split-dose regimen could be an alternative strategy for CDDP-ineligible patients; however, the optimal regimen needs to be determined in future studies. •Split-dose regimen dramatically reduced CDDP-induced AKI.•Split-dose regimen partially attenuated CDDP-induced sCKI.•The impact of split dosing on nephrotoxicity may depend on the regimen.•Split-dose regimen could be an alternative strategy for CDDP-ineligible patients.