title: Pharmacokinetic and pharmacodynamic modelling of the effects of glimepiride on insulin secretion and glucose lowering in healthy humans.
abstract: Glimepiride is an oral sulfonylurea antihyperglycaemic agent. We used pharmacokinetic-pharmacodynamic (PK-PD) modelling to analyse the relationship between plasma glimepiride concentration, insulin secretion and glucose lowering to determine the effects of the drug in healthy volunteers. A single 2-mg oral dose of glimepiride was administered to six healthy volunteers. The control group received a placebo. All subjects consumed 12 g of sugar immediately after drug administration in order to standardize the initial plasma glucose levels. Serial blood sampling was performed for 9 h after oral dosing. Plasma glimepiride, insulin and glucose levels were determined by validated methods (LC/MS/MS assay, hexokinase method and radioimmunoassay respectively). Time courses of plasma glimepiride concentration, insulin secretion, and glucose lowering effects were analysed by means of PK-PD modelling with the ADAPT II program. The time course of the plasma concentrations followed a two-compartmental model with a lag time. The glimepiride concentration peaked at 191.5 ng/mL at approximately 4 h after administration. The maximal increase in insulin secretion was 9.98 mIU/L and the maximal decrease in plasma glucose was 19.33 mg/dL. Both peak effects occurred at approximately 2.5 h after drug intake. The glucose disappearance model was used to analyse glimepiride's insulin secretion and glucose lowering effects. The PK-PD model described well the relationship between plasma glimepiride and its insulin secretion and hypoglycaemic effects in healthy volunteers.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, Korea.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Yun
authors.forename: H-C
authors.initials: HC
authors.lastname: Park
authors.forename: W
authors.initials: W
authors.lastname: Kang
authors.forename: K-I
authors.initials: KI
authors.lastname: Kwon
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D013453:Sulfonylurea Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds; C057619:glimepiride