Jauregizar Nerea, Quintana Antonio, Suarez Elena, Raczka Ewa, de la Fuente Leire, Calvo Rosario
Department of Pharmacology, Faculty of Medicine, University of the Basque Country, Leioa, Spain.
Gerontology. 2003 Jul-Aug;49(4):205-14. doi: 10.1159/000070400.
The importance of studying the effects of age on the pharmacokinetics and pharmacodynamics of lerisetron - a new 5-hydroxytryptamine-3 (serotonin) receptor antagonist - comes from the facts that lerisetron will be administered to patients that are being treated with cytotoxic drugs and that the elderly frequently suffer from neoplastic diseases.
The present study was designed to explore the effects of age on the pharmacokinetics and pharmacodynamics of lerisetron by using an aged rat model. A mixed-effects population study was carried out in order to analyze the sparse data and to create covariate models which could be used to derive dosage recommendations.
Fischer 344 rats (n = 44) were divided into three groups, depending on their age: 5, 13, and 25 months. Blood samples were collected before administration of 200 micro g/kg of lerisetron for measurements of albumin, alpha(1)-acid glycoprotein, and unbound fraction of lerisetron. The lerisetron plasma concentrations were measured by high-performance liquid chromatography. A two-compartment model was fitted to the data using the nonlinear mixed-effects computer program WinNonMix. The population analysis was performed with the complete set of the collected data, and the potential sources of variability in the population parameters were investigated. Additionally, a pharmacodynamic study was performed. The effect of lerisetron (inhibition of the von Bezold-Jarisch reflex) was evaluated in young, adult, and senescent Fischer 344 rats.
The mean values of the individual Bayes estimates of the parameters showed a decrease in total clearance and distribution volume of the central compartment in old rats. The lerisetron free (unbound) fraction remained unchanged among the groups, and there were no significant differences in alpha(1)-acid glycoprotein levels. The concentration-effect relationship was best described by a sigmoid E(max) model. Since the drug concentration in plasma at half-maximal effect (EC(50)) decreased in old rats, an increased sensitivity to the effect of lerisetron in old animals could be expected.
Both pharmacokinetic changes (decreased volume of distribution and clearance and increased elimination half-life) and pharmacodynamic alterations (decrease in total and unbound EC(50)) may be responsible for the different responses to lerisetron observed in old rats.
研究年龄对新型5-羟色胺-3（血清素）受体拮抗剂来立司琼药代动力学和药效学的影响具有重要意义，原因在于来立司琼将用于接受细胞毒性药物治疗的患者，且老年人常患肿瘤疾病。
本研究旨在通过使用老年大鼠模型探索年龄对来立司琼药代动力学和药效学的影响。开展了一项混合效应群体研究，以分析稀疏数据并创建可用于推导剂量建议的协变量模型。
将44只Fischer 344大鼠根据年龄分为三组：5个月、13个月和25个月。在给予200μg/kg来立司琼前采集血样，用于测量白蛋白、α1-酸性糖蛋白以及来立司琼的游离分数。采用高效液相色谱法测量来立司琼血浆浓度。使用非线性混合效应计算机程序WinNonMix对数据拟合二室模型。利用收集到的完整数据集进行群体分析，并研究群体参数变异性的潜在来源。此外，进行了一项药效学研究。在年轻、成年和老年Fischer 344大鼠中评估了来立司琼（抑制贝佐尔德-雅里什反射）的作用。
参数的个体贝叶斯估计平均值显示，老年大鼠中央室的总清除率和分布容积降低。各组中来立司琼的游离（未结合）分数保持不变，α1-酸性糖蛋白水平无显著差异。浓度-效应关系最好用S形E(max)模型描述。由于老年大鼠血浆中药物浓度在半数最大效应（EC50）时降低，预计老年动物对来立司琼作用的敏感性增加。
药代动力学变化（分布容积和清除率降低以及消除半衰期延长）和药效学改变（总EC50和未结合EC50降低）可能是老年大鼠对来立司琼观察到不同反应的原因。
