Safety assessment of multi-drug exposure: acute toxicity study of atorvastatin, ramipril, and BQ-123 combination in rats

Background: Combination cardiovascular therapies such as atorvastatin, ramipril, and endothelin-A receptor antagonists are increasingly used to improve clinical outcomes; however, their concurrent administration may introduce unforeseen pharmacodynamic and pharmacokinetic interactions. To date, no acute toxicity evaluation of this three-drug combination has been reported. Methodology: An acute toxicity study was conducted in female Wistar rats in accordance with OECD Guideline 423. A single intraperitoneal dose of atorvastatin (10 mg/kg), ramipril (1 mg/kg), and BQ-123 (1 mg/kg) was administered to a test group (n = 3), while controls received vehicle only (normal saline, 0.9% NaCl). Animals were monitored for 14 days for clinical signs of toxicity, mortality, body-weight changes, and behavioral changes. Gross necropsy and histopathological examinations of major organs were performed on Day 14. Result and Discussion: No mortality or clinical signs of toxicity were observed throughout the study. Body-weight progression in treated rats was consistent with that of the control group, demonstrating normal physiological growth. Gross pathological examination revealed no organ abnormalities or injection-site reactions. Histopathological analysis confirmed intact tissue architecture in the liver, kidney, heart, lungs, spleen, brain, stomach, and intestines. The absence of clinical, physiological, and histological alterations suggests that the atorvastatin–ramipril–BQ-123 combination does not induce acute systemic or organ toxicity at the tested dose. Findings indicate no synergistic or additive toxicity from co-administration, although further repeated-dose and biochemical assessments are necessary to characterize long-term safety. Conclusion: A single intraperitoneal administration of atorvastatin, ramipril, and BQ-123 was well tolerated in rats, classified as low acute hazard per OECD 423. Additional sub-acute and chronic studies are recommended to support therapeutic safety.