Non-linear pharmacokinetic modelling of intravenous elgodipine.

药代动力学 米氏-门汀动力学 消除速率常数 分配量 配送量 化学 滞后时间 血红蛋白 分布(数学) 内分泌学 内科学 色谱法 生物化学 医学 生物 酶分析 数学 数学分析 生物系统
作者
de la Motte S,X Alberich,Francisco Harrison
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期刊:PubMed 卷期号:37 (1): 20-7 被引量:1
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OBJECTIVE, SUBJECTS AND METHODS: The 1,4-dihydropyridine elgodipine was given as continuous infusion at various rates (5, 10, 15, 20, 40 microg/kg/h for 48, 48, 48, 24, or 6 h, respectively) to five groups of 6-12 healthy male subjects (total 42). Elgodipine plasma concentrations were measured with HPLC in 20-24 samples from each subject. Concentrations increased overproportionally with dose. Non-compartmental and compartmental evaluations were made. A two-compartment model with lag time and Michaelis-Menten term for elimination was found to be appropriate.Based on Michaelis-Menten parameters and concentration time courses during infusions, the elimination appeared to be saturated already at low dosages. There appeared to be two distinct subpopulations with two-fold differences in the maximal elimination velocity. In 9/42 subjects, more frequently in the groups with lower infusion rates, the model failed and the Michaelis-Menten term had to be replaced with a constant rate to fit. A dose-dependent increase in the volume of distribution and differences in and difficulties with estimations of the Michaelis-Menten constant KM might indicate a non-linear plasma protein binding. The transfer rate constants to or from the peripheral compartment correlated with blood hemoglobin or creatinine and bilirubin concentrations, respectively.The results indicated that tissue distribution and protein binding had marked influence on the plasma concentrations and, thus, attenuated the impact of saturation in the elimination.

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