Am. Stijnen et al., INCREASED SENSITIVITY TO THE ANTICONVULSANT EFFECT OF VALPROATE IN AGING BN BIRIJ RATS, Pharmaceutical research, 10(7), 1993, pp. 1046-1051
The aim of the present investigations was to study the influence of in
creasing age on the pharmacodynamics of valproate in BN/BiRij rats, ap
plying a threshold for electrically induced localized seizure activity
as a measure of the anticonvulsant effect. Seven groups of healthy ma
le BN/BiRij rats were used, aged 3, 6, 12, 19, 25, 31, and 37 months.
Individual plasma concentration versus anticonvulsant effect relations
hips were determined during a continuous intravenous infusion of sodiu
m valproate at a rate of 5.5 mg/min/kg. The infusion was terminated wh
en the anticonvulsant effect intensity had reached the maximum attaina
ble level or at a total infusion time of three hours. A nonlinear rela
tionship between valproate concentration and anticonvulsant effect int
ensity was observed with no maximal effect in the concentration range
up to 1200 mg.L-1. With increasing age a parallel shift in the concent
ration versus anticonvulsant effect relationships toward lower concent
rations occurred. Thus increasing age appears to be associated with an
increased sensitivity to the anticonvulsant effect of valproate.