The effects of age and dose on the pharmacokinetics of ketoprofen were evaluated in young adult and senescent male Fischer 344 rats following intravenous administration of 2.5 and 10 mg kg-1. Plasma concentrations were measured by HPLC and free ketoprofen determined by equilibrium dialysis. The glucuronidation of ketoprofen was investigated in a preparation of rat liver microsomes and kinetic analysis of UDP-glucuronyltransferase was carried out by determining the initial rate of metabolic activity as a function of ketoprofen concentration. Mean plasma clearance CLfree and steady-state volume of distribution Vssfree calculated from unbound plasma ketoprofen concentrations were significantly lower in the aged rat, suggesting reduced metabolic activity and decreased ketoprofen binding to tissue components, respectively. Plasma protein binding demonstrated an age-dependent decline due to decreases in both albumin concentration and binding affinity. Thus, plasma clearance CL and steady-state volume of distribution Vss changes were insignificant when total plasma concentrations were examined, due to the greater free fraction of ketoprofen in the plasma of senescent rats. The maximal rate of ketoprofen glucuronidation by hepatic microsomes was reduced whereas the affinity of the metabolic enzymes for the compound was unaffected by age. Dose had a marked effect on the disposition of ketoprofen as well. Saturation of elimination pathways and tissue binding sites contributed to significant declines in CLfree and Vssfree with increasing dose. Likewise, concentration-dependent plasma protein binding occurred, reflecting saturation of albumin binding. Thus, changes in the pharmacokinetic parameters based on total drug concentrations were offset by the increase in the unbound fraction of ketoprofen.

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The effects of age and dose on the pharmacokinetics of naproxen were evaluated in young and senescent male Fischer 344 rats after 2.5 and 25 mg/kg doses. Pharmacokinetic parameters based on free naproxen concentrations demonstrated a significant decrease in free clearance and free steady-state volume of distribution in the aged rats. In vitro enzyme kinetic studies also demonstrated an age-related decline in the metabolic activity and affinity of the metabolic enzymes for naproxen in the aged rats. Plasma protein binding studies revealed a larger free fraction of drug in the plasma of senescent rats. Total clearance and steady-state volume of distribution were indistinguishable between young and old rats owing to the higher free fraction in aged rats. Dose had a significant effect with free clearance and free volume of distribution decreasing as dose increased. The binding of naproxen to plasma proteins was dependent on drug concentration. Unlike the parameters based on free naproxen concentrations, total plasma clearance and volume of distribution increased with increasing dose, due to the nonlinear protein binding.

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