Gaudreault J, Varin F, Pollack G M
Faculté de Pharmacie, Université de Montréal, Canada.
J Pharm Sci. 1996 Sep;85(9):999-1004. doi: 10.1021/js9503183.
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.
三唑仑（TZ）是一种用于治疗失眠的三唑并苯二氮䓬类药物，具有显著的抗惊厥特性。尽管该药物广泛使用，但缺乏详细的药代动力学-药效学信息，尤其是关于癫痫活动抑制方面。此前描述TZ处置的方法特异性有限，且浓度-抗惊厥效应关系尚未明确。当前研究旨在采用特定的高效液相色谱法检测TZ的处置情况，并评估Sprague-Dawley大鼠中抗惊厥效应与浓度之间的关系。通过推注或输注给药后对TZ的药代动力学进行了表征；在另一个实验中，用戊四氮诱导的癫痫发作评估了TZ的药效学。TZ的全身处置可用二室模型描述；全身清除率范围为2.45至(5.30)L/h/kg，稳态分布容积范围为2.10至(4.02)L/kg,平均驻留时间范围为47至65分钟。浓度-效应关系可用简单的Emax模型很好地描述：Emax表示为TZ给药后与给药前戊四氮惊厥阈值剂量的比值，为9.9±0.7，血清和全脑组织中的EC50值分别为10.0±4.6 ng/mL和34.8±9.0 ng/g。在单剂量条件下，TZ在大鼠戊四氮癫痫模型中是一种非常有效的抗惊厥药物。
