Pharmacokinetics - Effect Relations of Glibenclamide and its Metabolites in Humans

Abstract: Glibenclamide (Gb) is the most commonly employed sulphonylurea worldwide for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). There has been uncertainty concerning its pharmacokinetics (PK) and pharmacodynamics (PD). Numerous long-lasting hypoglycemic reactions, which have sometimes been fatal, have been reported and have been difficult to reconsile with an allegedly short elimination half-life of Gb and presumedly low hypoglycemic activity of the metabolites, 4-trans-hydroxy-glibenclamide (M1) and 3-cis-hydroxy-glibenclamide (M2). Therefore, the objective of this thesis was to investigate the pharmacokinetics and concentration - effect relations of Gb and these two major metabolites. A simple liquid chromatographic method was developed for the analysis of low concentrations of Gb (1 ng/mL) and the two metabolites (5 ng/mL). The method was shown to be suitable for pharmacokinetic studies on Gb and its metabolites. The terminal elimination half-life of Gb was examined in 10 NIDDM subjects after cessation of long-term treatment, and it was concluded that the elimination of Gb during therapeutic conditions and chronic dosing is slower than previously thought. The long terminal half-life may help to explain why Gb may sometimes provoke long-lasting hypoglycemic reactions, and the result adds support to the clinical experience that Gb has a relatively long effect duration and supports the use of once-daily dosage of Gb. The PK of Gb and of its metabolites per se after intravenous administration was studied and compared in 8 healthy volunteers. It was concluded that the two Gb metabolites have similar PK except for volume of distribution (V) and renal clearance (CL). The PK of Gb and its metabolites was investigated and compared in 11 diabetic patients with impaired renal function (IRF) and 11 diabetic patients with normal renal function (NRF). It was concluded that very small amounts of M1 and M2 were excreted in the urine in the IRF group, and that the fraction excreted correlated significantly with renal function. CL/F for Gb was higher in the IRF group than in the NRF control group. Biliary excretion of Gb and metabolites seems likely. The hypoglycemic and insulin-releasing effect of M1 and M2 was assessed after intravenous administration of each metabolite in a placebo-controlled, randomized, single-blind crossover study. It was found that both metabolites have a marked hypoglycemic effect. The relationship between serum concentrations of Gb, M1 and M2 and their respective effects on blood glucose levels was studied. While there was no simple, direct relationship between drug concentrations and the hypoglycemic effect, consideration of PK and PD time dependencies by means of population PK/PD modelling demonstrated a relationship, involving both Gb and its active metabolites. It was concluded that the major metabolites contribute to the hypoglycemic effect subsequent in vivo formation in the body, that at low concentrations they may have higher activity and a longer effect duration than the parent drug per se. This should be clinically relevant.