Age- and dose-dependent naproxen disposition in Fischer 344 rats

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.