Hepatorenal Toxicity of Different Dose of Ketorolac Administration in Adult Male Rats: A Preclinical Study
Hepatorenal Toxicity of Different Dose of Ketorolac
Sažetak
Background/Aim: Ketorolac is a potent non-steroidal anti-inflammatory drug (NSAID) that can inhibit cyclooxygenase activity and prostaglandin synthesis, thereby reducing pain and inflammation. The aim of this study was to investigate the hepatorenal toxicity of ketorolac administration in adult male rats.
Methods: Twenty-four adult male Wistar rats were randomly assigned to three groups (n=8 per group): a control group receiving normal saline (1 mL/kg), a low-dose ketorolac group (10 mg/kg), and a high-dose ketorolac group (20 mg/kg). The animals were maintained under standard housing conditions for 3 weeks after the last treatment. Blood samples were collected under anesthesia, and serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine (Cr) were measured using commercial kits and a BT 1000 Biotectica analyzer.
Results: Compared to the control group, the low-dose ketorolac group did not show a significant increase in ALT and AST levels, but the high-dose ketorolac group exhibited a significant elevation in these hepatic enzymes (P<0.05). Both the low-dose and high-dose ketorolac groups demonstrated a significant increase in BUN and Cr levels compared to the control group, with the high-dose group showing a more pronounced elevation in these renal parameters (P<0.05).
Conclusion: The findings of this study suggest that high-dose ketorolac administration can induce hepatotoxic and nephrotoxic effects, as evidenced by the increased levels of liver and kidney function markers in adult male rats. These results highlight the importance of careful monitoring and dose optimization when using ketorolac in clinical settings.
Reference
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15- McGill MR. The past and present of serum aminotransferases and the future of liver injury biomarkers. EXCLI J 2016; 15:817-828. doi: 10.17179/excli2016-800.
16- Youssef EM, Wu GY. Subnormal Serum Liver Enzyme Levels: A Review of Pathophysiology and Clinical Significance. J Clin Transl Hepatol 2024; 12:428-435. doi: 10.14218/JCTH.2023.00446.
17- Sriuttha P, Sirichanchuen B, Permsuwan U. Hepatotoxicity of Nonsteroidal Anti-Inflammatory Drugs: A Systematic Review of Randomized Controlled Trials. Int J Hepatol 2018; 2018:5253623. doi: 10.1155/2018/5253623.
18- Rostom A, Goldkind L, Laine L. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. Clin Gastroenterol Hepatol 2005; 3:489-98. doi: 10.1016/s1542-3565(04)00777-3.
19- Lapeyre-Mestre M, de Castro AM, Bareille MP, Del Pozo JG, Requejo AA, Arias LM, et al. Non-steroidal anti-inflammatory drug-related hepatic damage in France and Spain: analysis from national spontaneous reporting systems. Fundam Clin Pharmacol 2006; 20:391-5. doi: 10.1111/j.1472-8206.2006.00416.x.
20- Rivera-Espinosa L, Muriel P, Ordaz Gallo M, Pérez-Urizar J, Palma-Aguirre A, Castañeda-Hernández G. Ketorolac pharmacokinetics in experimental cirrhosis by bile duct ligation in the rat. Ann Hepatol 2003; 2:175-81.
21- Lu W, Cheng F, Jiang J, Zhang C, Deng X, Xu Z, et al. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach. Sci Rep 2015; 5:8114. doi: 10.1038/srep08114.
22- Bessone F. Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? World J Gastroenterol 2010; 16:5651-61. doi: 10.3748/wjg.v16.i45.5651.
23- Donati M, Conforti A, Lenti MC, Capuano A, Bortolami O, Motola D, et al. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy. Br J Clin Pharmacol 2016; 82:238-48. doi: 10.1111/bcp.12938.
24- Lacroix I, Lapeyre-Mestre M, Bagheri H, Pathak A, Montastruc JL. Nonsteroidal anti-inflammatory drug-induced liver injury: a case-control study in primary care. Fundam Clin Pharmacol 2004; 18:201-6. doi: 10.1111/j.1472-8206.2004.00224.x.
25- Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc 2014; 89:95-106.
26- Soleimanpour M, Imani F, Safari S, Sanaie S, Soleimanpour H, Ameli H, Alavian SM. The Role of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in the Treatment of Patients with Hepatic Disease: A Review Article. Anesth Pain Med 2016; 6:e37822. doi: 10.5812/aapm.37822.
27- Rubenstein JH, Laine L. Systematic review: the hepatotoxicity of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 2004; 20:373-80. doi: 10.1111/j.1365-2036.2004.02092.x.
28- Aithal GP, Day CP. Nonsteroidal Anti-Inflammatory Drug–Induced Hepatotoxicity. Clinics in Liver Disease 2007; 11: 563-575. doi: 10.1016/j.cld.2007.06.004.
29- Ingrasciotta Y, Sultana J, Giorgianni F, Fontana A, Santangelo A, Tari DU, et al. Association of individual non-steroidal anti-inflammatory drugs and chronic kidney disease: a population-based case control study. PLoS One 2015; 10:e0122899. doi: 10.1371/journal.pone.0122899.
30- Ungprasert P, Cheungpasitporn W, Crowson CS, Matteson EL. Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies. Eur J Intern Med 2015; 26:285-91. doi: 10.1016/j.ejim.2015.03.008.
31- Lafrance JP, Miller DR. Selective and non-selective non-steroidal anti-inflammatory drugs and the risk of acute kidney injury. Pharmacoepidemiol Drug Saf 2009; 18:923-31. doi: 10.1002/pds.1798.
32- Hörl WH. Nonsteroidal Anti-Inflammatory Drugs and the Kidney. Pharmaceuticals (Basel) 2010; 3:2291-2321. doi: 10.3390/ph3072291.
33- Galli G, Panzetta G. Case report: reversible acute renal failure following therapy with both ketorolac (non-selective non-steroidal anti-inflammatory drug NSAID) and celecoxib (COX-2 selective) in the same patient. G Ital Nefrol 2002; 19:199-203.
34- Brater DC. Anti-inflammatory agents and renal function. Semin Arthritis Rheum 2002; 32:33-42. doi: 10.1053/sarh.2002.37216.
35- Dixit M, Doan T, Kirschner R, Dixit N. Significant Acute Kidney Injury Due to Non-steroidal Anti-inflammatory Drugs: Inpatient Setting. Pharmaceuticals (Basel) 2010; 3:1279-1285. doi: 10.3390/ph3041279.
36- Perazella MA, Buller GK. NSAID nephrotoxicity revisited: acute renal failure due to parenteral ketorolac. South Med J 1993; 86:1421-4. doi: 10.1097/00007611-199312000-00025.
37- Drożdżal S, Lechowicz K, Szostak B, Rosik J, Kotfis K, Machoy-Mokrzyńska A, et al. Kidney damage from nonsteroidal anti-inflammatory drugs-Myth or truth? Review of selected literature. Pharmacol Res Perspect 2021; 9:e00817. doi: 10.1002/prp2.817.
38- Hall ST, Mangram AJ, Barletta JF. Identification of Risk Factors for Acute Kidney Injury from Intravenous Ketorolac in Geriatric Trauma Patients. World J Surg 2022; 46:98-103. doi: 10.1007/s00268-021-06320-z.
39- Aitken HA, Burns JW, McArdle CS, Kenny GN. Effects of ketorolac trometamol on renal function. Br J Anaesth 1992; 68:481-5. doi: 10.1093/bja/68.5.481.
40- Waterbury LD, Silliman D, Jolas T. Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium. Curr Med Res Opin 2006; 22:1133-40. doi: 10.1185/030079906X112471.
41- Takahashi K, Patel AK, Nagai S, Safwan M, Putchakayala KG, Kane WJ, et al. Perioperative Ketorolac Use: A Potential Risk Factor for Renal Dysfunction After Live-Donor Nephrectomy. Ann Transplant 2017; 22:563-569. doi: 10.12659/aot.904762.
42- Freedland SJ, Blanco-Yarosh M, Sun JC, Hale SJ, Elashoff DA, Rajfer J, et al. Effect of ketorolac on renal function after donor nephrectomy. Urology 2002; 59:826-30. doi: 10.1016/s0090-4295(02)01514-5.
43- Buckley MM, Brogden RN. Ketorolac. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 1990; 39:86-109.
44- Macario A, Lipman AG. Ketorlac in the era of cyclo-oxygenase-2 selective nonsteroidal anti-inflammatory drugs: a systematic review of efficacy, side effects, and regulatory issues. Pain Med 2001; 2:336-51. doi: 10.1046/j.1526-4637.2001.01043.x.
2- Marzuillo P, Calligaris L, Amoroso S, Barbi E. Narrative review shows that the short-term use of ketorolac is safe and effective in the management of moderate-to-severe pain in children. Acta Paediatr 2018; 107:560-67. doi: 10.1111/apa.14189.
3- Maslin B, Lipana L, Roth B, Kodumudi G, Vadivelu N. Safety Considerations in the Use of Ketorolac for Postoperative Pain. Curr Drug Saf 2017; 12:67-73. doi: 10.2174/1574886311666160719154420.
4- Butcher B, Hutchings E, Fazekas B, Clark K, Rowett D, Currow D. Opioid-sparing effects of ketorolac in palliative care patients receiving opioids for chronic cancer-related pain: A systematic literature review. Palliat Med 2022; 36:71-80. doi: 10.1177/02692163211045310.
5- Vonkeman HE, van de Laar MA. Nonsteroidal anti-inflammatory drugs: adverse effects and their prevention. Semin Arthritis Rheum 2010; 39:294-312. doi: 10.1016/j.semarthrit.2008.08.001.
6- Wongrakpanich S, Wongrakpanich A, Melhado K, Rangaswami J. A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly. Aging Dis 2018; 9:143-150. doi: 10.14336/AD.2017.0306.
7- Ribeiro H, Rodrigues I, Napoleão L, Lira L, Marques D, Veríssimo M, et al. Non-steroidal anti-inflammatory drugs (NSAIDs), pain and aging: Adjusting prescription to patient features. Biomed Pharmacother 2022; 150:112958. doi: 10.1016/j.biopha.2022.112958.
8- Cao YL, Tian ZG, Wang F, Li WG, Cheng DY, Yang YF, et al. Characteristics and clinical outcome of nonsteroidal anti-inflammatory drug-induced acute hepato-nephrotoxicity among Chinese patients. World J Gastroenterol 2014; 20:13956-65. doi: 10.3748/wjg.v20.i38.13956.
9- Mariano F, Cogno C, Giaretta F, Deambrosis I, Pozza S, Berardino M, et al. Urinary protein profiles in ketorolac-associated acute kidney injury in patients undergoing orthopedic day surgery. Int J Nephrol Renovasc Dis 2017; 10:269-274. doi: 10.2147/IJNRD.S137102.
10- Othman AI, Abdel-Ghaffar A, Mahmoud AM. Ketorolac- and warfarin-induced renal toxicity: ultrastructural and biochemical study. J Basic Appl Zool 2019; 80: 1-9. doi: 10.1186/s41936-019-0106-2.
11- Bories M, Bacle A, Gilardi H, Le Corre P. Risk of acute kidney injury by initiation of non-steroidal anti-inflammatory drugs in hospitalised patients treated with diuretics and renin-angiotensin-aldosterone system inhibitors. Eur J Hosp Pharm 2022; 29:359-361. doi: 10.1136/ejhpharm-2020-002550.
12- Domínguez-Oliva A, Hernández-Ávalos I, Martínez-Burnes J, Olmos-Hernández A, Verduzco-Mendoza A, Mota-Rojas D. The Importance of Animal Models in Biomedical Research: Current Insights and Applications. Animals (Basel) 2023; 13:1223. doi: 10.3390/ani13071223.
13- Jota Baptista CV, Faustino-Rocha AI, Oliveira PA. Animal Models in Pharmacology: A Brief History Awarding the Nobel Prizes for Physiology or Medicine. Pharmacology 2021; 106:356-368. doi: 10.1159/000516240.
14- Kalas MA, Chavez L, Leon M, Taweesedt PT, Surani S. Abnormal liver enzymes: A review for clinicians. World J Hepatol 2021; 13:1688-1698. doi: 10.4254/wjh.v13.i11.1688.
15- McGill MR. The past and present of serum aminotransferases and the future of liver injury biomarkers. EXCLI J 2016; 15:817-828. doi: 10.17179/excli2016-800.
16- Youssef EM, Wu GY. Subnormal Serum Liver Enzyme Levels: A Review of Pathophysiology and Clinical Significance. J Clin Transl Hepatol 2024; 12:428-435. doi: 10.14218/JCTH.2023.00446.
17- Sriuttha P, Sirichanchuen B, Permsuwan U. Hepatotoxicity of Nonsteroidal Anti-Inflammatory Drugs: A Systematic Review of Randomized Controlled Trials. Int J Hepatol 2018; 2018:5253623. doi: 10.1155/2018/5253623.
18- Rostom A, Goldkind L, Laine L. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. Clin Gastroenterol Hepatol 2005; 3:489-98. doi: 10.1016/s1542-3565(04)00777-3.
19- Lapeyre-Mestre M, de Castro AM, Bareille MP, Del Pozo JG, Requejo AA, Arias LM, et al. Non-steroidal anti-inflammatory drug-related hepatic damage in France and Spain: analysis from national spontaneous reporting systems. Fundam Clin Pharmacol 2006; 20:391-5. doi: 10.1111/j.1472-8206.2006.00416.x.
20- Rivera-Espinosa L, Muriel P, Ordaz Gallo M, Pérez-Urizar J, Palma-Aguirre A, Castañeda-Hernández G. Ketorolac pharmacokinetics in experimental cirrhosis by bile duct ligation in the rat. Ann Hepatol 2003; 2:175-81.
21- Lu W, Cheng F, Jiang J, Zhang C, Deng X, Xu Z, et al. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach. Sci Rep 2015; 5:8114. doi: 10.1038/srep08114.
22- Bessone F. Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? World J Gastroenterol 2010; 16:5651-61. doi: 10.3748/wjg.v16.i45.5651.
23- Donati M, Conforti A, Lenti MC, Capuano A, Bortolami O, Motola D, et al. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy. Br J Clin Pharmacol 2016; 82:238-48. doi: 10.1111/bcp.12938.
24- Lacroix I, Lapeyre-Mestre M, Bagheri H, Pathak A, Montastruc JL. Nonsteroidal anti-inflammatory drug-induced liver injury: a case-control study in primary care. Fundam Clin Pharmacol 2004; 18:201-6. doi: 10.1111/j.1472-8206.2004.00224.x.
25- Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc 2014; 89:95-106.
26- Soleimanpour M, Imani F, Safari S, Sanaie S, Soleimanpour H, Ameli H, Alavian SM. The Role of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in the Treatment of Patients with Hepatic Disease: A Review Article. Anesth Pain Med 2016; 6:e37822. doi: 10.5812/aapm.37822.
27- Rubenstein JH, Laine L. Systematic review: the hepatotoxicity of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 2004; 20:373-80. doi: 10.1111/j.1365-2036.2004.02092.x.
28- Aithal GP, Day CP. Nonsteroidal Anti-Inflammatory Drug–Induced Hepatotoxicity. Clinics in Liver Disease 2007; 11: 563-575. doi: 10.1016/j.cld.2007.06.004.
29- Ingrasciotta Y, Sultana J, Giorgianni F, Fontana A, Santangelo A, Tari DU, et al. Association of individual non-steroidal anti-inflammatory drugs and chronic kidney disease: a population-based case control study. PLoS One 2015; 10:e0122899. doi: 10.1371/journal.pone.0122899.
30- Ungprasert P, Cheungpasitporn W, Crowson CS, Matteson EL. Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies. Eur J Intern Med 2015; 26:285-91. doi: 10.1016/j.ejim.2015.03.008.
31- Lafrance JP, Miller DR. Selective and non-selective non-steroidal anti-inflammatory drugs and the risk of acute kidney injury. Pharmacoepidemiol Drug Saf 2009; 18:923-31. doi: 10.1002/pds.1798.
32- Hörl WH. Nonsteroidal Anti-Inflammatory Drugs and the Kidney. Pharmaceuticals (Basel) 2010; 3:2291-2321. doi: 10.3390/ph3072291.
33- Galli G, Panzetta G. Case report: reversible acute renal failure following therapy with both ketorolac (non-selective non-steroidal anti-inflammatory drug NSAID) and celecoxib (COX-2 selective) in the same patient. G Ital Nefrol 2002; 19:199-203.
34- Brater DC. Anti-inflammatory agents and renal function. Semin Arthritis Rheum 2002; 32:33-42. doi: 10.1053/sarh.2002.37216.
35- Dixit M, Doan T, Kirschner R, Dixit N. Significant Acute Kidney Injury Due to Non-steroidal Anti-inflammatory Drugs: Inpatient Setting. Pharmaceuticals (Basel) 2010; 3:1279-1285. doi: 10.3390/ph3041279.
36- Perazella MA, Buller GK. NSAID nephrotoxicity revisited: acute renal failure due to parenteral ketorolac. South Med J 1993; 86:1421-4. doi: 10.1097/00007611-199312000-00025.
37- Drożdżal S, Lechowicz K, Szostak B, Rosik J, Kotfis K, Machoy-Mokrzyńska A, et al. Kidney damage from nonsteroidal anti-inflammatory drugs-Myth or truth? Review of selected literature. Pharmacol Res Perspect 2021; 9:e00817. doi: 10.1002/prp2.817.
38- Hall ST, Mangram AJ, Barletta JF. Identification of Risk Factors for Acute Kidney Injury from Intravenous Ketorolac in Geriatric Trauma Patients. World J Surg 2022; 46:98-103. doi: 10.1007/s00268-021-06320-z.
39- Aitken HA, Burns JW, McArdle CS, Kenny GN. Effects of ketorolac trometamol on renal function. Br J Anaesth 1992; 68:481-5. doi: 10.1093/bja/68.5.481.
40- Waterbury LD, Silliman D, Jolas T. Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium. Curr Med Res Opin 2006; 22:1133-40. doi: 10.1185/030079906X112471.
41- Takahashi K, Patel AK, Nagai S, Safwan M, Putchakayala KG, Kane WJ, et al. Perioperative Ketorolac Use: A Potential Risk Factor for Renal Dysfunction After Live-Donor Nephrectomy. Ann Transplant 2017; 22:563-569. doi: 10.12659/aot.904762.
42- Freedland SJ, Blanco-Yarosh M, Sun JC, Hale SJ, Elashoff DA, Rajfer J, et al. Effect of ketorolac on renal function after donor nephrectomy. Urology 2002; 59:826-30. doi: 10.1016/s0090-4295(02)01514-5.
43- Buckley MM, Brogden RN. Ketorolac. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 1990; 39:86-109.
44- Macario A, Lipman AG. Ketorlac in the era of cyclo-oxygenase-2 selective nonsteroidal anti-inflammatory drugs: a systematic review of efficacy, side effects, and regulatory issues. Pain Med 2001; 2:336-51. doi: 10.1046/j.1526-4637.2001.01043.x.
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2025/11/19
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Rubrika
Originalni rad / Original article