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

Astha Jaiswal; Phool  Chandra

doi:10.69857/joapr.v14i2.1947

Authors

Astha Jaiswal Teerthanker Mahaveer College of Pharmacy, Teerthanker Mahaveer University, Moradabad-244001, India
Phool Chandra Teerthanker Mahaveer College of Pharmacy, Teerthanker Mahaveer University, Moradabad-244001, India

DOI:

https://doi.org/10.69857/joapr.v14i2.1947

Keywords:

Acute toxicity, atorvastatin, ramipril, BQ-123, OECD 423, polypharmacy, Wistar rats, safety assessment

Abstract

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.

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References

Patel K, Irizarry-Caro JA, Khan A, Holder T, Salako D, Goyal P, Kwak MJ. Definition of polypharmacy in heart failure: a scoping review of the literature. Cardiol. Res., 15, 75–85 (2024) https://doi.org/10.14740/cr1636

Sirenko Y, Rekovets O. The impact of statins adding to the fixed combination antihypertensive therapy on the arterial stiffness in patients with moderate and severe hypertension. Int. J. Cardiol. Cardiovasc. Risk Prev., 18, 200190 (2023) https://doi.org/10.1016/j.ijcrp.2023.200190

Elsiad EA, Abd El Aal HA, Salem HA, El-Yamany MF, Rabie MA. Liraglutide attenuates atorvastatin-induced hepatotoxicity by restoring GLP-1R expression and activating Nrf2 and autophagy pathways in Wistar rats. Toxics, 13, 594 (2025) https://doi.org/10.3390/toxics13070594

Zhou L, Wu B, Bian Y, Lu Y, Zou Y, Lin S, Li Q, Liu C. Hepatotoxicity associated with statins: a retrospective pharmacovigilance study based on the FAERS database. PLoS One, 20, e0327500 (2025) https://doi.org/10.1371/journal.pone.0327500

Bouchenaki H, Danigo A, Bernard A, Bessaguet F, Richard L, Sturtz F, Balayssac D, Magy L, Demiot C. Ramipril alleviates oxaliplatin-induced acute pain syndrome in mice. Front. Pharmacol., 12, 712442 (2021) https://doi.org/10.3389/fphar.2021.712442

Chen Z, Zhang X, Lv S, Xing Z, Shi M, Li X, Chen M, Zuo S, Tao Y, Xiao G, Liu J, He Y. Treatment with endothelin-A receptor antagonist BQ123 attenuates acute inflammation in mice through T-cell-dependent polymorphonuclear myeloid-derived suppressor cell activation. Front. Immunol., 12, 641874 (2021) https://doi.org/10.3389/fimmu.2021.641874

Strickland J, Haugabrooks E, Allen DG, Balottin LB, Hirabayashi Y, Kleinstreuer NC, Kojima H, Nishizawa C, Prieto P, Ratzlaff DE, Jeong J, Lee J, Yang Y, Lin P, Sullivan K, Casey W. International regulatory uses of acute systemic toxicity data and integration of new approach methodologies. Crit. Rev. Toxicol., 53, 385–411 (2023) https://doi.org/10.1080/10408444.2023.2240852

Kojima H, Nakada T, Yagami A, Todo H, Nishimura J, Yagi M, Yamamoto K, Sugiyama M, Ikarashi Y, Sakaguchi H, Yamaguchi M, Hirota M, Aizawa S, Nakagawa S, Hagino S, Hatao M. A step-by-step approach for assessing acute oral toxicity without animal testing for additives of quasi-drugs and cosmetic ingredients. Curr. Res. Toxicol., 4, 100100 (2023) https://doi.org/10.1016/j.crtox.2022.100100

OECD. Test No. 423: Acute oral toxicity – acute toxic class method. OECD Publishing (2023) https://doi.org/10.1787/9789264071001-en

Park J, Kwon OS, Cho SY, Paick JS, Kim SW. Chronic administration of atorvastatin could partially ameliorate erectile function in streptozotocin-induced diabetic rats. PLoS One, 12, e0172751 (2017) https://doi.org/10.1371/journal.pone.0172751

Karahalil B, Hare E, Koç G, Uslu İ, Şentürk K, Özkan Y. Hepatotoxicity associated with statins. Arh. Hig. Rada Toksikol., 68, 254–260 (2017) https://doi.org/10.1515/aiht-2017-68-2994

Bouchenaki H, Bernard A, Bessaguet F, Frachet S, Richard L, Sturtz F, Magy L, Bourthoumieu S, Demiot C, Danigo A. Neuroprotective effect of ramipril is mediated by AT2 in a mouse model of paclitaxel-induced peripheral neuropathy. Pharmaceutics, 14, 848 (2022) https://doi.org/10.3390/pharmaceutics14040848

Zhang X, Chen Z, Zuo S, Sun H, Li X, Lu X, Xing Z, Chen M, Liu J, Xiao G, He Y. Endothelin-A receptor antagonist alleviates allergic airway inflammation via the inhibition of ILC2 function. Front. Immunol., 13, 835953 (2022) https://doi.org/10.3389/fimmu.2022.835953

Strickland J, Clippinger AJ, Brown J, Allen D, Jacobs A, Matheson J, Lowit A, Reinke EN, Johnson MS, Quinn MJ Jr, Mattie D, Fitzpatrick SC, Ahir S, Kleinstreuer N, Casey W. Status of acute systemic toxicity testing requirements and data uses by U.S. regulatory agencies. Regul. Toxicol. Pharmacol., 94, 183–196 (2018) https://doi.org/10.1016/j.yrtph.2018.01.022

Murwanti R, Nurrochmad A, Gani AP, Sasmito E, Edwina AE, Chandra MK, Suryawan FH, Wardana AR, Natalia, Budiningsih JLSR. Acute and subchronic oral toxicity evaluation of herbal formulation: Piper crocatum Ruiz and Pav., Typhonium flagelliforme (Lodd.) Blume, and Phyllanthus niruri L. in Sprague-Dawley rats. J. Toxicol., 2023, 7511397 (2023) https://doi.org/10.1155/2023/7511397

Kutsarova S, Mehmed A, Cherkezova D, Stoeva S, Georgiev M, Petkov T, Chapkanov A, Schultz TW, Mekenyan OG. Automated read-across workflow for predicting acute oral toxicity: I. The decision scheme in the QSAR toolbox. Regul. Toxicol. Pharmacol., 125, 105015 (2021) https://doi.org/10.1016/j.yrtph.2021.105015

Zarei MH, Lorigooini Z, Amini Khoei H, Bijad E. Acute oral toxicity assessment of galbanic acid in albino rat according to OECD 425 TG. Toxicol. Rep., 11, 111–115 (2023) https://doi.org/10.1016/j.toxrep.2023.07.001

Niyomchan A, Chatgat W, Chatawatee B, Keereekoch T, Issuriya A, Jaisamut P, Chusri S, Kunworarath N. Safety evaluation of the polyherbal formulation NawaTab: acute and subacute oral toxicity studies in rats. Evid. Based Complement. Alternat. Med., 2023, 9413458 (2023) https://doi.org/10.1155/2023/9413458

Yun JW, Kwon E, Kim YS, Kim SH, You JR, Kim HC, Park JS, Che JH, Lee SK, Jang JJ, Kim HH, Kang BC. Assessment of acute, 14-day, and 13-week repeated oral dose toxicity of Tiglium seed extract in rats. BMC Complement. Altern. Med., 18, 251 (2018) https://doi.org/10.1186/s12906-018-2315-5

Singh A, Ilango K. Acute and sub-chronic toxicity study of novel polyherbal formulation in non-alcoholic fatty liver using Wistar rats. Future Sci. OA, 10, FSO910 (2024) https://doi.org/10.2144/fsoa-2023-0118

Feng X, Chen S, Li J, Dai X, Chen Y, Xie B, Zhang Z, Ren L, Yan L. Evaluation of acute and 28-day repeated dose toxicity of Tolypocladium sinense soft capsule in Sprague-Dawley rats. Drug Chem. Toxicol., 48, 1045–1056 (2025) https://doi.org/10.1080/01480545.2024.2427766

Intatham S, Taychaworaditsakul W, Khonsung P, Chansakaow S, Jaijoy K, Lertprasertsuke N, Soonthornchareonnon N, Sireeratawong S. Safety evaluation for acute and chronic oral toxicity of Maha Pigut Triphala containing three medicinal fruits in Sprague-Dawley rats. Biology, 13, 1005 (2024) https://doi.org/10.3390/biology13121005

Giri S, Chandra P. Therapeutic potential of natural flavonoids: pharmacological targets, signaling pathways, molecular mechanisms, and clinical perspective on Parkinson’s disease. Curr. Drug Ther., 20, 315–331 (2024) https://doi.org/10.2174/0115748855292178240223100534

Sewell F, Ragan I, Horgan G, Andrew D, Holmes T, Manou I, Müller BP, Rowan T, Schmitt BG, Corvaro M. New supporting data to guide the use of evident toxicity in acute oral toxicity studies (OECD TG 420). Regul. Toxicol. Pharmacol., 146, 105517 (2024) https://doi.org/10.1016/j.yrtph.2023.105517

Ebbo AA, Sani D, Suleiman MM, Ahmad A, Hassan AZ. Acute and sub-chronic toxicity evaluation of the crude methanolic extract of Diospyros mespiliformis Hochst ex A. DC (Ebenaceae) and its fractions. Toxicol. Rep., 7, 1138–1144 (2022) https://doi.org/10.1016/j.toxrep.2020.08.028

Varshney KK, Gupta JK, Srivastava R. Unveiling the molecular mechanism of diosmetin and its impact on multifaceted cellular signaling pathways. Protein Pept. Lett., 31, 275–289 (2024) https://doi.org/10.2174/0109298665294109240323033601

Malik MK, Bhatt P, Singh J, Kaushik RD, Sharma G, Kumar V. Preclinical safety assessment of chemically cross-linked modified mandua starch: acute and sub-acute oral toxicity studies in Swiss albino mice. ACS Omega, 7, 35506–35514 (2022) https://doi.org/10.1021/acsomega.2c01309