Jauregizar N, Calvo R, Suarez E, Quintana A, Raczka E, Lukas J C
Department of Pharmacology, Faculty of Medicine, University of the Basque, Leioa, Vizcaya, Spain.
Pharm Res. 2001 Jun;18(6):838-45. doi: 10.1023/a:1011096714860.
To examine the effect of changes in plasma alpha1-acid glycoprotein (AAG) levels on the pharmacokinetics (PK) and pharmacodynamics (PD) of lerisetron, a novel serotonin 5-HT3 receptor antagonist, in the rat.
After subcutaneous administration of turpentine oil, AAG was significantly elevated compared with controls. The PK of unchanged lerisetron (UL; high-performance liquid chromatography with radioactivity monitoring) and total lerisetron (TL; unchanged + changed, scintillation counting) was characterized post intravenous (i.v.) 14C lerisetron (50 microg/kg) in control and turpentine oil pretreated rats. The PK (0-180 min) was described by a two-compartmental model. Protein binding of lerisetron in vitro was measured using an ultrafiltration technique. The effect of lerisetron (5 microg/kg, i.v.) over 180 min was measured in anesthetized rats (control and pretreated) with the Bezold-Jarisch reflex (inhibition of bradycardia after 16 microg/kg serotonin i.v.) as the endpoint. PD parameters were estimated by sigmoid Emax models.
The unbound fraction was significantly diminished in pretreated rats (mean +/- SEM) (6.60 +/- 1.23% vs. control 14.4 +/- 1.40%, P < 0.05). Volume of distribution (V) and clearance for UL and TL were significantly decreased when compared to the controls (P < 0.0001 for UL and P < 0.05 for TL). Plasma clearance based on unbound concentration for UL did not differ between groups but the unbound V and steady-state unbound V remained decreased (P < 0.05 and P < 0.0001). Pretreated rats showed a significantly diminished drug effect: the area under the E-t curve over 180 min was (mean +/- SEM) 5,189 +/- 657.7 in control animals vs. 3,486 +/- 464.4 in the pretreated group (P < 0.05). The EC50 (concentration at half maximum effect) for UL and TL were increased in pretreated rats and were not compensated when the unbound concentration was used.
An increase in AAG causes alterations in the PK and PD of lerisetron, and because this is not compensated with the unbound concentration, we suggest that mechanisms not linked to protein binding may be involved.
研究血浆α1-酸性糖蛋白（AAG）水平变化对新型5-羟色胺5-HT3受体拮抗剂来立司琼在大鼠体内的药代动力学（PK）和药效学（PD）的影响。
皮下注射松节油后，与对照组相比，AAG显著升高。在对照大鼠和经松节油预处理的大鼠静脉注射（i.v.）14C来立司琼（50μg/kg）后，对未变化的来立司琼（UL；放射性监测高效液相色谱法）和总来立司琼（TL；未变化+变化的，闪烁计数法）的PK进行了表征。PK（0 - 180分钟）用二室模型描述。采用超滤技术测定来立司琼的体外蛋白结合率。以来立司琼（5μg/kg，i.v.）作用180分钟后对麻醉大鼠（对照和预处理）的贝佐尔德-雅里什反射（静脉注射16μg/kg 5-羟色胺后心动过缓的抑制）为终点，测定其作用效果。PD参数通过S形Emax模型估算。
预处理大鼠的游离分数显著降低（平均值±标准误）（6.60±1.23%对对照组14.4±1.40%，P < 0.05）。与对照组相比，UL和TL的分布容积（V）和清除率显著降低（UL为P < 0.0001，TL为P < 0.05）。基于UL游离浓度的血浆清除率在两组之间无差异，但游离V和稳态游离V仍降低（P < 0.05和P < 0.0001）。预处理大鼠的药物作用显著减弱：对照动物180分钟内E-t曲线下面积（平均值±标准误）为5,189±657.7，预处理组为3,486±464.4（P < 0.05）。预处理大鼠中UL和TL的EC50（最大效应一半时的浓度）升高，且使用游离浓度时未得到补偿。
AAG升高导致来立司琼的PK和PD发生改变，且由于未与游离浓度得到补偿，我们认为可能涉及与蛋白结合无关的机制。
