Abstract

The pharmacokinetics of ibuprofen after 2.5 and 25 mg/kg doses were examined in young adult (5 months) and senescent (24 months) male Fischer 344 rats. Plasma concentrations of ibuprofen were determined by HPLC and protein binding was measured by equilibrium dialysis. The cytochrome P-450-mediated metabolism of ibuprofen was investigated in vitro using microsomal protein from rat liver as the source of drug-metabolizing enzymes. Dose had a marked effect on the disposition of ibuprofen, with free plasma clearance (CLfree) decreasing 40% and apparent free steady-state volume of distribution (Vssfree) decreasing 58% as dose increased from 2.5 to 25 mg/kg. These changes reflected saturation of elimination pathways and tissue-binding sites. The binding of ibuprofen to plasma proteins was dependent on drug concentration. Unlike the parameters based on free ibuprofen concentrations, there were no significant changes in total plasma clearance (CL) or steady-state volume of distribution (Vss) due to the nonlinear protein binding. Aging also had a significant effect on ibuprofen pharmacokinetics. Decreases in CLfree and Vssfree of 42 and 51%, respectively, suggested a reduction in metabolic activity and binding of ibuprofen to tissue components in the aged rats. A decrease in plasma protein binding in the old rats was related to decreases in albumin concentration and the number of albumin binding sites. Thus, due to the greater free fraction of ibuprofen in the plasma of aged rats, CL increased significantly, whereas Vss remained unaffected by age when total plasma concentrations were examined. The metabolic capacity exhibited an age-related decline of 42%, whereas the affinity of the metabolic enzymes for ibuprofen was unaffected by age.