Increased sensitivity to the anticonvulsant effect of valproate in aging BN/BiRij rats

• Published in: Pharmaceutical research Vol. 10; no. 7; p. 1046
• Main Authors: Stijnen, A M, Hovinga, S, Langemeijer, M W, Hoogerkamp, A, van Bezooijen, C F, Danhof, M
• Format: Journal Article
• Language: English
• Published: United States 01.07.1993
• Subjects: Aging - physiology; Animals; Anticonvulsants - pharmacology; Chromatography, Gas; Electroshock; Infusions, Intravenous; Male; Rats; Rats, Inbred BN; Valproic Acid - administration & dosage; Valproic Acid - pharmacokinetics; Valproic Acid - pharmacology
• ISSN: 0724-8741
• DOI: 10.1023/A:1018975025417

The aim of the present investigations was to study the influence of increasing age on the pharmacodynamics of valproate in BN/BiRij rats, applying a threshold for electrically induced localized seizure activity as a measure of the anticonvulsant effect. Seven groups of healthy male BN/BiRij rats were used, aged 3, 6, 12, 19, 25, 31, and 37 months. Individual plasma concentration versus anticonvulsant effect relationships were determined during a continuous intravenous infusion of sodium valproate at a rate of 5.5 mg/min/kg. The infusion was terminated when the anticonvulsant effect intensity had reached the maximum attainable level or at a total infusion time of three hours. A nonlinear relationship between valproate concentration and anticonvulsant effect intensity was observed with no maximal effect in the concentration range up to 1200 mg.L-1. With increasing age a parallel shift in the concentration versus anticonvulsant effect relationships toward lower concentrations occurred. Thus increasing age appears to be associated with an increased sensitivity to the anticonvulsant effect of valproate.