Dose-dependent pharmacokinetics of ibuprofen in the rat

The linearity of the pharmacokinetics of ibuprofen was examined in male Sprague-Dawley rats given iv bolus doses of 10, 20, and 50 mg/kg ibuprofen. Plasma and urine concentrations of ibuprofen and its two major metabolites, OH-ibuprofen and COOH-ibuprofen, were determined by HPLC and the binding of ibuprofen to plasma proteins was measured by an ultrafiltration technique. The systemic plasma clearance (CLtot) of ibuprofen was dose-dependent and decreased from 0.29 to 0.14 liter/hr/kg primarily as a result of a 65% decrease in the partial metabolic clearance to OH-ibuprofen while the average mean residence time (MRTtot) increased approximately 35% over the 10-50 mg/kg dosage range. Since there were no dose-dependent changes in the apparent steady state volume of distribution (Vss,tot), the mean harmonic half-life increased from 1.7-2.8 hr over the dosage range studied. The binding of ibuprofen to plasma proteins was relatively independent of concentration up to 90 mg/liter (mean free fraction approximately 5.5%), but became markedly concentration-dependent thereafter (free fraction up to 25.4% at 411 mg/liter). The mean recovery of total ibuprofen in the urine over 24 hours at 10 mg/kg was 62.1% and decreased by 24% and 40% at 50 and 20 mg/kg, respectively. This dose-dependent decrease in the percentage excreted in the urine was primarily due to a reduction in the recovery of OH-ibuprofen slightly offset by a small, but significant, increase in the urinary excretion of COOH-ibuprofen between 10 and 50 mg/kg. The apparent pharmacokinetic parameters based on free, unbound concentrations of ibuprofen were also dose-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)