Although animal models, such as electroshock
seizures,
pentylenetetrazol (PTZ)-induced
seizures and the rotorod test, are widely employed in the search for and evaluation of new
anticonvulsant drugs, the important role of diverse technical,
biological and pharmacological factors in the interpretation of results obtained with these models is often not recognized. In order to delineate factors other than strain, sex, age, diet, climate, and circadian rhythms, which are generally known, a series of studies was undertaken. In the experiments described here, the influence of administration vehicles and
drug formulations on bioavailability, potency and time course of
anticonvulsant drugs was studied in mice. Two standard
anticonvulsant drugs,
primidone and
carbamazepine, with poor aqueous solubility were used for these experiments, because water insolubility is a common problem in the laboratory evaluation of
anticonvulsant agents. Since vehicles, especially organic
solvents or
detergents, may exert effects of their own, sensitive electroshock and PTZ seizure threshold tests were used for the assessment of vehicle-related actions. Of various aqueous or lipophilic vehicles tested, only
glycofurol increased seizure thresholds, when concentrations exceeding 10% were administered. However, even at a concentration of 30%, the solubilizer did not exert measurable effects in the maximal electroshock seizure (MES) test in mice, but markedly potentiated the effect of
primidone. In contrast,
polyethylene glycol 400 (
PEG 400) up to a concentration of 30% did not affect electrical or chemical seizure thresholds nor did it alter the pharmacological potency of
primidone. When
primidone or
carbamazepine were administered as a
suspension in a
Tween/water vehicle, their
anticonvulsant effects were considerably lower compared to
injections of the same doses as a
solution.(ABSTRACT TRUNCATED AT 250 WORDS)