title: Exacerbation of celecoxib-induced renal injury by concomitant administration of misoprostol in rats.
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.
authors.affiliation: Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Dustin L
authors.initials: DL
authors.lastname: Cooper
authors.affiliation: Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Derek E
authors.initials: DE
authors.lastname: Murrell
authors.affiliation: Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Conder
authors.affiliation: Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Palau
authors.affiliation: Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Grace E
authors.initials: GE
authors.lastname: Campbell
authors.affiliation: Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Lynch
authors.affiliation: Department of Pathology, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: James W
authors.initials: JW
authors.lastname: Denham
authors.affiliation: Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Angela V
authors.initials: AV
authors.lastname: Hanley
authors.affiliation: Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Kenny W
authors.initials: KW
authors.lastname: Bullins
authors.affiliation: Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Panus
authors.affiliation: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Krishna
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Sam
authors.initials: S
authors.lastname: Harirforoosh
mesh_terms: D000284:Administration, Oral; D000450:Aldosterone / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D000068579:Celecoxib; D004573:Electrolytes / Q000652:urine; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007674:Kidney Diseases / Q000139:chemically induced*; D016595:Misoprostol / Q000008:administration & dosage / Q000009:adverse effects*; D011188:Potassium / Q000652:urine; D011720:Pyrazoles / Q000009:adverse effects*; D051381:Rats; D012964:Sodium / Q000652:urine; D013449:Sulfonamides / Q000009:adverse effects*; D019210:Troponin I / Q000097:blood
chemical_list: D004573:Electrolytes; D011720:Pyrazoles; D013449:Sulfonamides; D019210:Troponin I; D016595:Misoprostol; D000450:Aldosterone; D012964:Sodium; D000068579:Celecoxib; D011188:Potassium