<abstract xmlns="http://www.w3.org/1999/xhtml">Rosuvastatin, a second generation 3-Hydroxy-3-Methyl Glutaryl Coenzyme-A reductase inhibitor, is widely used for the management of hypercholesterolemia. Rosuvastatin ethanolamine, developed by Cadila Healthcare Ltd., is a novel, chemically stable, and pharmaceutically acceptable salt, having better physiochemical properties than commercially available Rosuvastatin salt. The objective of the present study is to evaluate safety, tolerability, and toxicokinetic profile of novel salt. Therefore, four weeks repeated dose oral (gavage) toxicity and toxicokinetic study of Rosuvastatin ethanolamine was carried out. The drugs were administered once daily at salt corrected dose of 15, 40, and 100 mg/kg for four weeks. No signs of toxicity were observed during repeated (four weeks) oral administrations of Rosuvastatin ethanolamine in rats up to 40 mg/kg. Single male mortality was observed at 100 mg/kg dose. Microscopy finding in liver was minimal to mild bile ductular proliferation, single cell necrosis, and hepatocellular vacuolation of cytoplasm with associated statistically significant serum elevation of transaminase enzymes; AST, ALT, ALP, and/or liver functional marker; total bilirubin with at ≥40 mg/kg. The systemic exposures (AUC0–24 and Cmax) were not markedly different between males and females, or between the administration periods (except high dose, where exposure on day 28 was approximately 2 to 3 fold higher than that of day 1. In conclusion, Rosuvastatin ethanolamine exhibited toxicities to liver as the target organ at ≥40 mg/kg in this study. These adverse effects with associated exposures should be taken into consideration for the future assessing of potential Rosuvastatin toxicities.</abstract>

Rosuvastatin, a second generation 3-Hydroxy-3-Methyl Glutaryl Coenzyme-A reductase inhibitor, is widely used for the management of hypercholesterolemia. Rosuvastatin ethanolamine, developed by Cadila Healthcare Ltd., is a novel, chemically stable, and pharmaceutically acceptable salt, having better physiochemical properties than commercially available Rosuvastatin salt. The objective of the present study is to evaluate safety, tolerability, and toxicokinetic profile of novel salt. Therefore, four weeks repeated dose oral (gavage) toxicity and toxicokinetic study of Rosuvastatin ethanolamine was carried out. The drugs were administered once daily at salt corrected dose of 15, 40, and 100 mg/kg for four weeks. No signs of toxicity were observed during repeated (four weeks) oral administrations of Rosuvastatin ethanolamine in rats up to 40 mg/kg. Single male mortality was observed at 100 mg/kg dose. Microscopy finding in liver was minimal to mild bile ductular proliferation, single cell necrosis, and hepatocellular vacuolation of cytoplasm with associated statistically significant serum elevation of transaminase enzymes; AST, ALT, ALP, and/or liver functional marker; total bilirubin with at ≥40 mg/kg. The systemic exposures (AUC0–24 and Cmax) were not markedly different between males and females, or between the administration periods (except high dose, where exposure on day 28 was approximately 2 to 3 fold higher than that of day 1. In conclusion, Rosuvastatin ethanolamine exhibited toxicities to liver as the target organ at ≥40 mg/kg in this study. These adverse effects with associated exposures should be taken into consideration for the future assessing of potential Rosuvastatin toxicities.

Non-clinical safety evaluation of a novel pharmaceutical salt, rosuvastatin ethanolamine, in Wistar rats

Toxicology Section, Department of Non-clinical Research

Pathology Section, Department of Non-clinical Research

Drug Metabolism and Pharmacokinetics Section, Department of Biopharmaceutic

Interdisciplinary Toxicology

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Rosuvastatin, a second generation 3-Hydroxy-3-Methyl Glutaryl Coenzyme-A reductase inhibitor, is widely used for the management of hypercholesterolemia....

Non-clinical safety evaluation of a novel pharmaceutical salt, rosuvastatin ethanolamine, in Wistar rats

Published Online: Feb 20, 2020

Page range: 7 - 14

Received: Jan 16, 2018

Accepted: Mar 15, 2019

DOI: https://doi.org/10.2478/intox-2019-0002

Keywords
Rosuvastatin ethanolamine, toxicity study, toxicokinetic study, Wistar rat

© 2019 Jigneshkumar Vaghasiya et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Non-clinical safety evaluation of a novel pharmaceutical salt, rosuvastatin ethanolamine, in Wistar rats

Published Online: Feb 20, 2020

Page range: 7 - 14

Received: Jan 16, 2018

Accepted: Mar 15, 2019

DOI: https://doi.org/10.2478/intox-2019-0002

KeywordsRosuvastatin ethanolamine, toxicity study, toxicokinetic study, Wistar rat

© 2019 Jigneshkumar Vaghasiya et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Keywords
Rosuvastatin ethanolamine, toxicity study, toxicokinetic study, Wistar rat