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.