Effect of inflammation on kidney function and pharmacokinetics of COX-2 selective nonsteroidal anti-inflammatory drugs rofecoxib and meloxicam.
Chronic arthritis adversely affects glomerular function and nonsteroidal anti-inflammatory drugs (NSAIDs) reduce electrolyte urinary excretion. In addition, both acute and chronic inflammations may alter clearance of drugs. We studied (a) the effects of inflammation on the renal function and pharmacokinetics of rofecoxib and meloxicam; (b) whether inflammation could exacerbate reduced electrolytes excretion changes observed with NSAIDs; and (c) the influence of inflammation on distribution of these drugs into the kidney. Single oral doses of rofecoxib (10 mg kg(-1)), meloxicam (3 mg kg(-1)) or placebo were administered to normal or pre-adjuvant arthritic rats. Blood and urine samples were collected for the measurement of plasma nitrite, BUN and creatinine. The urinary excretion of sodium and potassium was also determined. Nitrite, BUN and plasma creatinine were increased starting on day 9 in the groups with inflammation. Sodium and potassium excretion rates were not affected by inflammation. Meloxicam did not alter the electrolyte excretion in any of the groups. Rofecoxib significantly decreased sodium and potassium excretion in normal rats and potassium excretion in inflamed rats. Inflammation significantly increased plasma concentrations of rofecoxib, but not meloxicam. The ratios of the kidney:plasma concentrations were not significantly altered by inflammation following either drug. Inflammation altered kidney function, demonstrated by increases in BUN and plasma creatinine. However, it did not influence the urinary electrolytes excretion. Since we have observed similar patterns of the effect of NSAIDs on kidney under healthy and inflammatory conditions, one may conclude that inflammation does not exacerbate the adverse effect.
Harirforoosh
Sam
S
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
Jamali
Fakhreddin
F
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000503:physiopathology*; D052246:Cyclooxygenase 2 Inhibitors / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology*; D007677:Kidney Function Tests; D007783:Lactones / Q000493:pharmacokinetics*; D008297:Male; D000077239:Meloxicam; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000493:pharmacokinetics*; D013843:Thiazines / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000493:pharmacokinetics*
D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D013450:Sulfones; D013843:Thiazines; D013844:Thiazoles; C116926:rofecoxib; D000077239:Meloxicam