Pharmacokinetics of high-dosage naproxen in elderly patients

After multiple oral doses of 500 mg naproxen twice daily, eight young healthy male volunteers and six male and female elderly patients participated in a pharmacokinetic study. Serum naproxen levels were measured by high-pressure liquid chromatography; protein-unbound drug was determined after equilibrium dialysis. A significantly lower maximal serum concentration (Cpeak), smaller area under the curve during one dose interval [AUC(0-12)], larger total body clearance (CL/F) and apparent volume of distribution (V/F body wt-1) were found for the total drug in elderly patients. The pharmacokinetics of the protein-unbound drug showed higher trough and peak concentrations, larger AUC(0-12)u, and smaller (CL/F)u and (V/F)u in the elderly patients. The unbound fraction (less than 1% of total naproxen) showed concentration dependency; in the elderly, a larger unbound fraction was found. Pharmacokinetic differences between the elderly and the young may be explained by a lower serum albumin concentration in the aged, together with a decrement in binding affinity of naproxen to albumin; moreover, the clearance of unbound drug was significantly reduced in the elderly (281 +/- 96 l/h) as compared with the young (713 +/- 164 l/h). We conclude that age-related factors increase serum unbound naproxen concentrations. It is, therefore, advisable to start treatment with naproxen in the elderly at a low dosage.