On the pharmacodynamics, pharmacokinetics and metabolism of sulphonylurea and its metabolites - with special reference to glibenclamide

Abstract: The pharmacodynamics (PD), pharmacokinetics (PK) and metabolism of the sulphonylurea(SU) and its metabolites (M1 and M2) , and of another SU, glipizide (Gz) were studied in diabetes patients and healthy volunteers. In one study Caucasians and Chinese were compared. Sensitive and selective methods for determination of drug levels and concentrations of insulin and proinsulin were used. The terminal half-life of Gb was calculated to be 15.0+/-6.7 h in 10 type 2 diabetes patients on high Gb dosage (10.5 mg or more). Blood glucose levels were reduced and serum insulin levels were increased by M1 and M2 i.v. in a single-dose study in 8 healthy volunteers. M1 had 75 % and M2 50 % of the blood glucose reducing effect of the parent compound. The PK of Gb (7.0 mg orally, single-dose) was studied in diabetes patients (11 in each group) with impaired (IRF) and normal renal function. AUC and Cmax of Gb were lower and the ratio of clearance over bioavailability (Cl/F) was higher in the IRF patients. M1 followed the opposite pattern. Much lower amounts of Gb metabolites were excreted in the urine in the IRF group indicating non-renal eliminations routes, probably biliary secretion. Minor differences in PD and PK were found between Caucasian and Chinese patients (10 in each group) with type 2 diabetes after administration of Gb (i.v. and orally), Gz (orally) or placebo in a single-dose study. The overall SU-induced glucose responses were similar. In 50 patients on chronic Gb medication at different daily dose levels (1.75-14.0 mg), Gb was capable to stimulate both insulin and proinsulin secretion. The effect was more pronounced in patients on a low dose, either because of less impaired beta-cells in those receiving low doses or due to reduced SU sensitivity in those on high dosage (down-regulation). In patients on a daily dose of 10.5 mg or more, serum metabolite levels of clinical relevance were demonstrated. The slow elimination and the high serum metabolite concentrations in patients on chronic Gb therapy may contribute to the long-lasting hypoglycaemic events sometimes seen in patients treated with Gb. Once daily dosage of Gb is justified. The diabetes patient should be offered a Gb dosage not exceeding 7 mg daily (HB 420). The same dosage principles may be used when Gb and Gz are prescribed to Caucasian and Chinese patients with type 2 diabetes.