Histomorphological and biochemical alterations on the liver of Wistar rats following co-administration of NSAIDs (Piroxicam, Diclofenac and Ibuprofen)

Non-steroidal anti-inflammatory drugs (NSAIDs) are an important therapeutic class of drugs widely used to suppress acute or chronic pains and  inflammatory diseases such as in rheumatoid arthritis (RA), osteoarthritis (OS) etc. The aim of this study was to investigate the random combination and  individual effect of COX-2 inhibitors (NSAIDs) on the liver. This study was conducted using a total of 40 adults Wistar rats. The rats were divided into eight  groups of 5 rats each. Group one was the control group, group 2 was given piroxicam (0.29mg/kg) daily, group 3 was given ibuprofen (5.71mg/kg) daily,  and group 4 received diclofenac (1.42mg/kg) daily. Group 5 received piroxicam (0.29mg/kg bodyweight) plus ibuprofen (0.58mg/kg), group 6 received  piroxicam (0.29mg/kg) plus diclofenac (1.42mg/kg) and group 7 received ibuprofen (0.58mg/kg) plus diclofenac (1.42mg/kg) respectively daily. Group 8  was given Piroxicam (0.29mg/kg bodyweight) plus Ibuprofen (5.71mg/kg) plus diclofenac (1.42mg/kg) daily. Intervention was over a period of 3days.  Animals were sacrificed after 24 hours and the liver tissues were excised, some were fixed in 10% neutral buffered formalin for histological studies while  others were placed in normal saline for biochemical analysis. The results revealed that there was no significant statistical difference in total bilirubin, ALT  and AST when compared to the control. This suggests that NSAIDs may have no significant effects on the liver for this regimen. Histological changes  observed were congested portal vein, haemorrhagic bile ducts, distortion of portal triad and sinusoids, and degeneration of hepatocytes. In conclusion,  NSAIDs may have harmful effect on the cytoarchitecture of the liver which can lead to liver damage especially when given in high doses and in  combination, but however it had no effect on liver function. 

[1]  Noah R. Flynn,et al.  Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics , 2020, Drug Metabolism and Disposition.

[2]  S. Owen,et al.  Pharmacology-informed prediction of the risk posed to fish by mixtures of non-steroidal anti-inflammatory drugs (NSAIDs) in the environment , 2020, Environment international.

[3]  P. Goswami,et al.  Development of new methods for determination of bilirubin , 2019, Journal of pharmaceutical and biomedical analysis.

[4]  Heshu Sulaiman Rahman,et al.  Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases , 2018, Front. Pharmacol..

[5]  A. Wongrakpanich,et al.  A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly , 2018, Aging and disease.

[6]  C. Fokunang,et al.  Overview of non-steroidal anti-inflammatory drugs (nsaids) in resource limited countries , 2018 .

[7]  Nagendra Singh Chauhan,et al.  Prodrugs of NSAIDs: A Review , 2017, The open medicinal chemistry journal.

[8]  R. Fontana,et al.  Liver injury from nonsteroidal anti‐inflammatory drugs in the United States , 2016, Liver international : official journal of the International Association for the Study of the Liver.

[9]  S. Alavian,et al.  The Therapeutic Use of Analgesics in Patients With Liver Cirrhosis: A Literature Review and Evidence-Based Recommendations , 2014, Hepatitis monthly.

[10]  N. Boer,et al.  Nonsteroidal Anti-Inflammatory Drug Associated Colopathy , 2013 .

[11]  Terry M. Therneau,et al.  Underestimation of liver-related mortality in the United States. , 2013, Gastroenterology.

[12]  G. Aithal,et al.  Hepatotoxicity related to antirheumatic drugs , 2011, Nature Reviews Rheumatology.

[13]  F. Bessone Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? , 2010, World journal of gastroenterology.

[14]  M. Munger,et al.  Polypharmacy and Combination Therapy in the Management of Hypertension in Elderly Patients with Co-Morbid Diabetes Mellitus , 2010, Drugs & aging.

[15]  M. Mikov,et al.  Diclofenac and ketoprofen liver toxicity in rat , 2008, European Journal of Drug Metabolism and Pharmacokinetics.

[16]  G. Aithal,et al.  Nonsteroidal anti-inflammatory drug-induced hepatotoxicity. , 2007, Clinics in liver disease.

[17]  A. Hamza Curcuma longa, Glycyrrhiza glabra and Moringa oleifera Ameliorate Diclofenac-induced Hepatoxicity in Rats , 2007 .

[18]  M. Dkhil,et al.  Piroxicam-induced hepatic and renal histopathological changes in mice , 2007, The Libyan journal of medicine.

[19]  Yang-Kyu Choi,et al.  Aspartate Aminotransferase (AST/GOT) and Alanine Aminotransferase (ALT/GPT) Detection Techniques , 2006, Sensors (Basel, Switzerland).

[20]  H. Motanis,et al.  Hepatotoxicity of anti-inflammatory and analgesic drugs: ultrastructural aspects , 2006, Acta Pharmacologica Sinica.

[21]  L. Laine,et al.  Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. , 2005, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[22]  A. D. Paul,et al.  Study of usage pattern of nonsteroidal anti-inflammatory drugs (NSAIDs) among different practice categories in Indian clinical setting , 2005, European Journal of Clinical Pharmacology.

[23]  L. Laine,et al.  The hepatotoxicity of non‐steroidal anti‐inflammatory drugs , 2004, Alimentary pharmacology & therapeutics.

[24]  Joe Kesterson,et al.  Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. , 2004, Gastroenterology.

[25]  R. Da Cas,et al.  Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs , 2003, BMJ : British Medical Journal.

[26]  J. Muntané,et al.  Orthotopic liver transplantation after subacute liver failure induced by therapeutic doses of ibuprofen , 2002, American Journal of Gastroenterology.

[27]  Y. Masubuchi,et al.  Role of mitochondrial permeability transition in diclofenac‐induced hepatocyte injury in rats , 2002, Hepatology.

[28]  M. Melato,et al.  The histopathology of non-steroidal anti-inflammatory drug induced gastroduodenal damage: correlation with Helicobacter pylori, ulcers, and haemorrhagic events , 2001, Journal of clinical pathology.

[29]  M. Pellett,et al.  Comparative Pharmacokinetics of Two Fast-Dissolving Oral Ibuprofen Formulations and a Regular-Release Ibuprofen Tablet in Healthy Volunteers , 2001 .

[30]  P. McGettigan,et al.  Current problems with non-specific COX inhibitors. , 2000, Current pharmaceutical design.

[31]  James H. Lewis,et al.  NSAID-INDUCED HEPATOTOXICITY , 1998 .

[32]  J. Castell,et al.  A study of the relative hepatotoxicity in vitro of the non-steroidal anti-inflammatory drugs ibuprofen, flurbiprofen and butibufen. , 1988, Xenobiotica; the fate of foreign compounds in biological systems.

[33]  Lloyd H. Michael,et al.  The Guide for the Care and Use of Laboratory Animals. , 2016, ILAR journal.

[34]  Ravi R. Alamchandani,et al.  A comparative survey study on current prescribing trends in non-steroidal anti-inflammatory drugs among practitioners in private set up and tertiary care teaching rural hospital , 2014 .

[35]  A. Rhodes Fixation of tissues , 2013 .

[36]  M. Bloomston,et al.  Liver anatomy. , 2010, The Surgical clinics of North America.

[37]  M. Pirmohamed,et al.  The role of cytochrome P450 enzymes in hepatic and extrahepatic human drug toxicity. , 1995, Pharmacology & therapeutics.