Exacerbation of celecoxib-induced renal injury by concomitant administration of misoprostol in rats
Authors: Kenny W Bullins
Derek E Murrell
Grace E Campbell
Victoria E Palau
Peter C Panus
Angela V Hanley
Krishna Singh
Christopher M Conder
Dustin L Cooper
James W Denham
Shaun P Lynch
Sam Harirforoosh
Journal: PLoS ONE (2014)
Discipline: Multidisciplinary
Keywords: Nonsteroidal anti-inflammatory drugs; NSAIDs; prostaglandin synthesis; misoprostol; celecoxib
Affiliations: Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee, United States of America., Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee, United States of America., Department of Pathology, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America., Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.

Abstract:  Nonsteroidal anti-inflammatory drugs (NSAIDs) can produce adverse effects by inhibiting prostaglandin (PG) synthesis. A PGE1 analogue, misoprostol, is often utilized to alleviate NSAID-related gastrointestinal side effects. This study examined the effect of misoprostol on celecoxib renal toxicity. Additionally, the effects of these drugs on cardiovascular parameters were evaluated. Four randomized rat groups were orally gavaged for 9 days, two groups receiving vehicle and two groups receiving misoprostol (100 ¬µg/kg) twice daily. Celecoxib (40 mg/kg) was co-administered once daily to one vehicle and one misoprostol group from days 3 to 9. Urine and blood samples were collected and blood pressure parameters were measured during the study period. Hearts and kidneys were harvested on final day. Day 2 urinary electrolyte samples revealed significant reductions in sodium excretion in misoprostol (0.12 ¬± 0.05 ¬µmol/min/100 g) and misoprostol+celecoxib groups (0.07 ¬± 0.02 ¬µmol/min/100 g). At day 3, all treatment groups showed significantly reduced sodium excretion. Potassium excretion diminished significantly in vehicle+celecoxib and misoprostol+celecoxib groups from day 3 onward. Urinary kidney injury molecule-1 levels were significantly increased in vehicle+celecoxib (0.65 ¬± 0.02 vs. 0.35 ¬± 0.07 ng/mL, p = 0.0002) and misoprostol+celecoxib (0.61 ¬± 0.06 vs. 0.37 ¬± 0.06 ng/mL, p = 0.0015) groups when compared to baseline; while plasma levels of cardiac troponin I increased significantly in vehicle+celecoxib (p = 0.0040) and misoprostol+misoprostol (p = 0.0078) groups when compared to vehicle+vehicle. Blood pressure parameters increased significantly in all misoprostol treated groups. Significant elevation in diastolic (p = 0.0071) and mean blood pressure (p = 0.0153) was noted in misoprostol+celecoxib compared to vehicle+celecoxib. All treatments produced significant tubular dilatation/necrosis compared to control. No significant myocardial changes were noticed; however, three animals presented with pericarditis. Kidney, heart, and plasma celecoxib levels revealed no significant change between vehicle+celecoxib and misoprostol+celecoxib. Concomitant misoprostol administration did not prevent celecoxib renal toxicity, and instead exacerbated renal side effects. Misoprostol did not alter plasma or tissue celecoxib concentrations suggesting no pharmacokinetic interaction between celecoxib and misoprostol. 

Retracted: No

PubPeer comments:
 Figure 11. * Red boxes: Two panels in A (vehicle + vehicle) and D (misoprostol + celecoxib) appear to look very similar to each other. Reported to the journal in October 2015, but no action taken as of today.  ,