Anticonvulsant pharmacodynamics and disposition of triazolam in rats.
Triazolam (TZ) is a triazolobenzodiazepine used in the treatment of insomnia that possesses significant anticonvulsant properties. Despite the widespread use of this drug, detailed pharmacokinetic-pharmacodynamic information is lacking, especially with respect to inhibition of seizure activity. TZ disposition has been described previously by methods with limited specificity, and the concentration-anticonvulsant effect relationship has not been characterized. The current studies were undertaken to examine TZ disposition with a specific HPLC method, and to evaluate the relationship between anticonvulsant effect and concentration in Sprague-Dawley rats. TZ pharmacokinetics were characterized after bolus or infusion administration; in a separate experiment, TZ pharmacodynamics were assessed with pentylenetetrazol-induced seizures. The systemic disposition of TZ could be described with a two-compartment model; systemic clearance ranged from 2.45 to 5.30 L/h/ kg, steady-state volume of distribution ranged from 2.10 to 4.02 L/kg, and mean residence time ranged from 47 to 65 min. The concentration-effect relationship was well described by a simple Emax model: Emax, expressed as the ratio of post-TZ to pre-TZ threshold convulsant doses of pentylenetetrazol, was 9.9 +/- 0.7, and the EC50 values were 10.0 +/- 4.6 ng/mL and 34.8 +/- 9.0 ng/g in serum and whole brain tissue, respectively. Under single-dose conditions, TZ is a very potent anticonvulsant in the rat pentylenetetrazol seizure model.
Gaudreault
J
J
Faculté de Pharmacie, Université de Montréal, Canada.
Varin
F
F
Pollack
G M
GM
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D051381:Rats; D017207:Rats, Sprague-Dawley; D014229:Triazolam / Q000493:pharmacokinetics / Q000494:pharmacology*
D000927:Anticonvulsants; D014229:Triazolam