DOSE-DEPENDENT PHARMACOKINETICS OF IBUPROFEN IN THE RAT

  • 1 March 1987
    • journal article
    • research article
    • Vol. 15  (2) , 151-154
Abstract
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 mesured 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. Unlike the parameters based on total ibuprofen concentrations, there was a significant decrease in the systemic plasma clearance based on free, unbound concentrations (CLfree) primarily due to the saturation in the hydroxylation of ibuprofen in the rat with increasing doses. In addition, the apparent unbound steady state volume of distribution (Vss,free) exhibited a dose-dependent decrease with increasing doses suggesting saturation in the binding of ibuprofen to tissue components. However, no dose-dependent changes were observed with the elimination rate constant (.beta.free) and MRTfree.