Extent of renal effect of cyclo-oxygenase-2-selective inhibitors is pharmacokinetic dependent.
Non-steroidal anti-inflammatory drugs (NSAIDs) cause renal side-effects. In the present study, we tested the hypothesis that the extent of the renal effects of cyclo-oxygenase (COX)-2-selective NSAIDs is linked to their pharmacokinetics. A single oral dose of rofecoxib (10 mg/kg), celecoxib (40 mg/kg), meloxicam (3 mg/kg) or placebo was administered to rats. Urinary excretion of electrolytes, a marker of renal effects, and plasma and kidney concentrations of NSAIDs were measured. Rofecoxib and celecoxib, but not meloxicam, significantly decreased urinary sodium and potassium excretion. There was a significant correlation between the area under the 24 h plasma concentration-time curve (AUC0-24) of rofecoxib and the change in sodium (r = -0.65; P < 0.02) and potassium (r = -0.82; P < 0.0006) excretion. The AUC0-24 of celecoxib was correlated with sodium (r = -0.80; P < 0.05) but not potassium excretion. The ratios of kidney to plasma drug concentrations were 1.72, 3.16 and 0.17 for rofecoxib, celecoxib and meloxicam, respectively. The renal effect of the COX-2-selective NSAIDs examined, marked by their ability to reduce the excretion of electrolytes, is influenced by systemic exposure to the drugs. The relatively higher distribution into the kidneys of rofecoxib and celecoxib compared with meloxicam suggests involvement of direct drug exposure in the kidneys in the adverse renal effect.
Harirforoosh
Sam
S
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Aghazadeh-Habashi
Ali
A
Jamali
Fakhreddin
F
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects*; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D000077239:Meloxicam; D010919:Placebos / Q000008:administration & dosage / Q000493:pharmacokinetics; D011188:Potassium / Q000652:urine; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000652:urine; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D013843:Thiazines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D010919:Placebos; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; D013843:Thiazines; D013844:Thiazoles; C116926:rofecoxib; D012964:Sodium; D000068579:Celecoxib; D011188:Potassium; D000077239:Meloxicam