EFFECTS OF AGE ON THE PHARMACODYNAMICS OF NAPROXEN IN THE RAT

The pharmacodynamics of naproxen were evaluated in 5- and 24-month-old male Fischer 344 rats. Plasma naproxen concentrations and thromboxane B-2 (TxB(2)) concentrations were measured as a function of time after intravenous administration of 25 mg/kg naproxen. Age-dependent altera tions in naproxen pharmacokinetics were attributed to significant redu ctions in free plasma clearance (CL(free)) and free steady-state volum e of distribution (Vss(free)), suggesting a decline in metabolic activ ity and naproxen binding to tissue components in aged rats, respective ly. The time course of TxB(2) production as a function of unbound napr oxen concentrations was described by a sigmoid E(max) model. Age had n o significant effect on the pharmacodynamic parameter E(max), the maxi mum percent inhibition of TxB(2) formation. Age also had no statistica lly significant effect on EC(50), the drug concentration producing 50% of the maximum effect, however, average EC(50) values were 35% higher in the aged rats. The duration of TxB(2) inhibition was unaffected by age, possibly owing to similar relative decreases in receptor sensiti vity (increased EC(50)) and increases in free naproxen concentrations (decreased free clearance and volume of distribution), Alternatively, the age-related changes in pharmacokinetic parameters were not of suff icient magnitude to produce a significant change in drug response. nap roxen, pharmacokinetics, pharmacodynamics, age, rats, thromboxane B-2, nonsteroidal anti-inflammatory drugs.