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.