Concentration-effect relations of glibenclamide and its active metabolites in man: modelling of Pharmacokinetics and Pharmacodynamics

作者：Tony Rydberg, Anders Hassel Jönsson, Mats O. Karlsson, Arne Melander · 发表于：British Journal of Clinical Pharmacology · 年份：1997 · DOI：10.1046/j.1365-2125.1997.00571.x · 被引用次数：65 · 研究领域：Pharmacogenetics and Drug Metabolism、Diabetes Treatment and Management、Diabetes, Cardiovascular Risks, and Lipoproteins

AIMS: The main purpose of this paper is to describe the relationship between serum concentrations of glibenclamide and its main metabolites and the effects on blood glucose levels, the clinically most relevant parameter to assess in diabetes. METHODS: Serum concentrations and blood glucose lowering effects (expressed as percent blood glucose reduction vs placebo) of glibenclamide (Gb) and its active metabolites, 4-trans-hydroxy-(M1) and 3-cis-hydroxy-glibenclamide (M2), were analysed in eight healthy subjects participating in a placebo-controlled, randomized, single-blind crossover study, using intravenous administration of each compound as well as oral administration of Gb. RESULTS: Plots of % blood glucose reduction vs log serum concentration demonstrated counter-clockwise hysteresis for parent drug and its metabolites. An effect compartment was linked to appropriate pharmacokinetic models and pharmacokinetic and pharmacodynamic modelling was used to fit the pharmacokinetics of Gb by both routes and the metabolites for each individual. Based on the individual concentration-time profiles a PK/PD-model was applied to all effect data simultaneously. An increase in the steady-state serum concentration when the effect is 50% of maximal, CEss50, was found in the sequence M1 (23 ng ml-1), M2 (37 ng ml-1) and Gb (108 ng ml-1). Corresponding interindividual variabilities expressed as CV% were 25%, 47% and 26%. The elimination rate constants from the effect site (kEO) were estimated ...