2003
   Verona, Italy

Absorption and plasma kinetics of multiple high oral doses of glucose: influence of glibenclamide.

MR, Ballester, MJ Barbanoj, R Antonijoan, M Yritia, M Valle.

Centre d´Investigació de Medicaments, Servei de Farmacologia Clínica, HSCSP. Departament de Farmacologia i Terapèutica, UAB. Barcelona (Spain).

Objective: To develop a population model to describe the absorption and plasma time profile of glucose when multiple high oral doses of glucose are administered in healthy volunteers and the lowering effect of two different formulations of glibenclamide (a second generation sulphonylurea, commonly used for type-2 diabetes treatment).

Methods: Twenty-four healthy volunteers of both sexes were enrolled in a placebo-controlled, randomized, single-blind, crossover study. After an overnight fast, 240ml of a 20% glucose solution was administered together with placebo, glibenclamide A (5mg) or glibenclamide B (5mg). Further, 60mL of 20% glucose solution was administered at 15min intervals up to 4h. Glucose plasma levels were assessed throughout Glucose analyzer (Hemoue®) before and at different times up to 16h postadministration. Population data analysis of glucose levels was performed employing NONMEM (version V) in three stages: (i) analysis of glucose absorption and plasma kinetics after its administration with placebo (ii) analysis of gibenclamide plasma kinetics (iii) modelling of glibenclamide effect. The effects of some of the collected covariates [age, gender, weight, creatinine clearance, smoking (either as continuous or categorical covariate)] were also examined. Results: Absorption of glucose was best modeled as a saturable process that follows Michaelis-Menten kinetics. Plasma levels of glucose were modeled employing a semi-physiological model: glucose levels were assumed to be due to the exogenous administration, and the endogenous synthesis and degradation in plasma. Taking into account the homeostatic processes that regulate glucose plasma levels, an extra compartment was added to the model representing the insuline. This compartment was assumed to have the same synthesis and degradation constant rate. Other assumptions of the model were (i) an increase in glucose levels induces an increase in the synthesis of insuline (linear model) (ii) insuline levels stimulates glucose degradation (linear model). After testing different models, the glibenclamide effect was incorporated as an inhibitory effect on the glucose degradation process.

Conclusions: Saturation is observed in the absorption process when administering high oral doses of glucose. None of the administered glibenclamide formulations showed an onset of action rapid enough to avoid the first peak observed in the glucose levels.