Sun L, Lau C E
Department of Chemistry, Rutgers, The State University of New Jersey (L.S.), 152 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.
Eur J Pharmacol. 2000 Jun 16;398(2):225-38. doi: 10.1016/s0014-2999(00)00277-6.
We examined the pharmacokinetics and pharmacodynamics of intravenous (1-5 mg/kg) and oral clozapine (2.5-10 mg/kg) in rats (terminal half-life=81.8 min; oral bioavailability=5.32%). Both dose- and concentration-effect relations of clozapine were characterized. Clozapine's effects were similar to those of benzodiazepines because of the similarity in effect-time profiles between the two classes of drugs. The IC(50) value increased as a function of dose; consequently, clozapine's relative potency decreased linearly with the logarithm of AUC((0-infinity)), or bioavailable dose regardless of route of administration. The IC(50) is an index for the sensitivity of behavioral performance to clozapine; relative potency provides an index for estimating the extent of acute tolerance. As IC(50) increases, relative potency decreases, and consequently, acute tolerance increases. Our results demonstrated that greater acute tolerance was observed for i.v. clozapine than for p.o. clozapine; however, clozapine exhibited a single concentration-effect relation across dose and route of administration after correcting for relative potencies.
我们研究了大鼠静脉注射（1 - 5毫克/千克）和口服氯氮平（2.5 - 10毫克/千克）的药代动力学和药效学（终末半衰期 = 81.8分钟；口服生物利用度 = 5.32%）。对氯氮平的剂量 - 效应关系和浓度 - 效应关系均进行了表征。由于两类药物在效应 - 时间曲线方面具有相似性，氯氮平的效应与苯二氮䓬类药物相似。IC(50)值随剂量增加而升高；因此，无论给药途径如何，氯氮平的相对效价随AUC((0 - ∞))或生物可利用剂量的对数呈线性下降。IC(50)是行为表现对氯氮平敏感性的指标；相对效价为估计急性耐受程度提供了一个指标。随着IC(50)升高，相对效价降低，因此急性耐受增加。我们的结果表明，静脉注射氯氮平比口服氯氮平观察到更大的急性耐受；然而，校正相对效价后，氯氮平在不同剂量和给药途径下呈现单一的浓度 - 效应关系。
