Jauregizar Nerea, Calvo Rosario, Suarez Elena, Quintana Antonio, Raczka Ewa, Lukas John C
Department of Pharmacology, Faculty of Medicine, University of the Basque Country, Leioa, Vizcaya 48940, Spain.
J Pharm Sci. 2002 Jan;91(1):41-52. doi: 10.1002/jps.1169.
The pharmacokinetics of lerisetron, a novel 5HT(3) antagonist, are studied together with its efficacy in inhibiting the serotonin (5-HT)-evoked transient bradycardia reflex (von Bezold-Jarisch reflex) in Sprague Dawley rats. [(14)C]Lerisetron (50, 100, and 200 microg/kg) was given to rats by intravenous (iv) injection and plasma levels of unchanged (UL) and total (unchanged + changed, TL) drug were measured by liquid chromatography with radioactivity monitoring and scintillation counting, respectively. Linearity of UL and TL pharmacokinetics over the dose range was established by noncompartmental analysis. Protein binding of lerisetron was measured in vitro by ultrafiltration. The unbound fraction was 14.4 +/- 1.4%. A nonlinear mixed effects ("population") bicompartmental pharmacokinetic analysis showed that volume of distribution and clearance (CL) were high for both forms of the drug, but CL was significantly smaller for TL [(mean +/- SEM) 0.014 +/- 0.03 L/min for UL versus 0.006 +/- 0.03 L/min for TL, p < 0.05)]. Large interindividual variabilities were observed for both forms. The response to lerisetron administration (inhibition of bradycardia) was evaluated at different doses (2, 3, 5, 6, and 10 microg/kg, iv) at times 2-180 min after dose administration and related to simulated concentrations. Inhibition was 100% 5 min after the 10-microg/kg dose and, 3 h later, it was still > 10%. Response to lerisetron was dose related in the range studied. Pharmacodynamic parameters were estimated by a sigmoid E(max) naive-pooled model. The parameters were also different between the two forms: EC(50) was 0.44 ng/mL (CV = 5.9%) for UL and 0.88 ng/mL (CV = 4.9%) for TL. We conclude that UL and TL pharmacokinetics were linear and that the differences in the kinetics and dynamics between the two forms suggest the presence of at least one metabolite.
研究了新型5-羟色胺（5HT）3拮抗剂雷司琼的药代动力学及其对Sprague Dawley大鼠中血清素（5-羟色胺，5-HT）诱发的短暂性心动过缓反射（贝佐尔德-雅里什反射）的抑制作用。通过静脉注射将[(14)C]雷司琼（50、100和200微克/千克）给予大鼠，并分别通过放射性监测的液相色谱法和闪烁计数法测量未变化（UL）和总（未变化+变化，TL）药物的血浆水平。通过非房室分析确定了剂量范围内UL和TL药代动力学的线性关系。通过超滤在体外测量雷司琼的蛋白结合率。未结合分数为14.4±1.4%。非线性混合效应（“群体”）双房室药代动力学分析表明，两种形式的药物分布容积和清除率（CL）都很高，但TL的CL明显较小[（平均值±标准误）UL为0.014±0.03升/分钟，TL为0.006±0.03升/分钟，p<0.05]。两种形式均观察到较大的个体间变异性。在给药后2至180分钟的不同剂量（2、3、5、6和10微克/千克，静脉注射）下评估雷司琼给药后的反应（心动过缓抑制），并与模拟浓度相关。10微克/千克剂量后5分钟抑制率为100%，3小时后仍>10%。在所研究的范围内，对雷司琼的反应与剂量相关。通过S形E(max)朴素合并模型估计药效学参数。两种形式的参数也不同：UL的EC(50)为0.44纳克/毫升（CV=5.9%），TL的EC(50)为0.88纳克/毫升（CV=4.9%）。我们得出结论，UL和TL药代动力学是线性的，两种形式之间的动力学和动态差异表明至少存在一种代谢物。
