ANTICONVULSANT PHARMACODYNAMICS AND DISPOSITION OF TRIAZOLAM IN RATS

Triazolam (TZ) is a triazolobenzodiazepine used in the treatment of in somnia that possesses significant anticonvulsant properties. Despite t he widespread use of this drug, detailed pharmacokinetic-pharmacodynam ic information is lacking, especially with respect to inhibition of se izure activity. TZ disposition has been described previously by method s with limited specificity, and the concentration-anticonvulsant effec t relationship has not been characterized. The current studies were un dertaken to examine TZ disposition with a specific HPLC method, and to evaluate the relationship between anticonvulsant effect and concentra tion in Sprague-Dawley rats. TZ pharmacokinetics were characterized af ter bolus or infusion administration; in a separate experiment, TZ pha rmacodynamics were assessed with pentylenetetrazol-induced seizures. T he systemic disposition of TZ could be described with a two-compartmen t model; systemic clearance ranged from 2.45 to 5.30 L/h/kg, steady-st ate volume of distribution ranged from 2.10 to 4.02 L/kg, and mean res idence time ranged from 47 to 65 min. The concentration-effect relatio nship was well described by a simple E(max) model: E(max), expressed a s the ratio of post-TZ to pre-TZ threshold convulsant doses of pentyle netetrazol, was 9.9 +/- 0.7, and the EC(50) values were 10.0 +/- 4.6 n g/mL and 34.8 +/- 9.0 ng/g in serum and whole brain tissue, respective ly. Under single-dose conditions, TZ is a very potent anticonvulsant i n the rat pentylenetetrazol seizure model.