Dosing-time dependent testicular toxicity of everolimus in mice.

Autor: Ozturk N; Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Beyazit-Istanbul, Turkey., Ozturk Civelek D; Department of Pharmacology, Faculty of Pharmacy, Bezmialem Vakif University, Fatih-Istanbul, Turkey., Sancar S; Department of Biology, Faculty of Science, Istanbul University, Vezneciler-Istanbul, Turkey., Kaptan E; Department of Biology, Faculty of Science, Istanbul University, Vezneciler-Istanbul, Turkey., Pala Kara Z; Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Beyazit-Istanbul, Turkey., Okyar A; Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Beyazit-Istanbul, Turkey. Electronic address: aokyar@istanbul.edu.tr.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2021 Oct 01; Vol. 165, pp. 105926. Date of Electronic Publication: 2021 Jul 07.
DOI: 10.1016/j.ejps.2021.105926
Abstrakt: The circadian timing system controls many biological functions in mammals including drug metabolism and detoxification, cell cycle events, and thus may affect pharmacokinetics, target organ toxicity and efficacy of medicines. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer drug that is effective against several cancers. The aim of this study was to investigate dosing-time dependent testicular toxicity of subacute everolimus administration in mice. C57BL/6 J male mice were synchronized with Light-Dark (12h:12 h) cycle, with Light-onset at Zeitgeber Time (ZT)-0. Everolimus (5 mg/kg/day) was administered orally to mice at ZT1 rest-span or ZT13 activity-span for 4 weeks. Body weight loss, clinical signs, changes in testicular weights, testis histology, spermatogenesis and proliferative activity of germinal epithelium of seminiferous tubules were examined. Steady-state everolimus concentrations in testes were determined with validated HPLC method. Everolimus toxicity was less severe following dosing at ZT13 compared to ZT1, as shown with least body weight loss (p<0.001), least reductions in testes weights (p<0.001) and least histopathological findings. Everolimus-induced histological changes on testes included vacuolisation and atrophy of germinal epithelium, and loss of germinal cell attachment. The severity of everolimus-induced histological toxicity on testes was significantly more evident in mice treated at ZT1 than ZT13 (p<0.001). Spermatogenic cell population significantly decreased when everolimus administered at ZT1 compared to ZT13 (p<0.001). Proliferative activity of germinal epithelium was significantly decreased due to treatment at ZT1 compared to ZT13 (p<0.001). Everolimus concentrations in testes indicated a pronounced circadian variation, which was greater in mice treated at ZT1 compared to ZT13 (p<0.05). Our study revealed dosing-time dependent testicular toxicity of everolimus in mice, which was greater in severity when everolimus administered at early rest-span (daytime-ZT1) than early activity-span (nighttime-ZT13). These findings support the concept of everolimus chronotherapy for minimizing reproductive toxicity and increasing the tolerability of everolimus, as a clinical advantage.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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