Modulation of the P-Glycoproein-Mediated Intestinal Secretion of Glibenclamide: In Vitro and In Vivo Assessments

P Srirangam,J Vidya Sagar

doi:10.4103/0975-1483.71632

Abstract

The everted gut sac method was used to assess the role of the P-glycoprotein (P-gp) on the intestinal secretion of glibenclamide, a prototype of drug used to treat diabetic mellitus. The study included the evaluation of a P-gp modulator carbamazepine used at equimolar doses in the rat. Furthermore, the influence of carbamazepine on the disposition kinetics of glibenclamide in plasma was characterized. For the in vitro experiments, ileal sacs were incubated with glibenclamide in the presence or absence of carbamazepine. In the in vivo experiments, albino rats of either sex were randomly allocated to two groups (n = 6) and oral treatment with glibenclamide (3.6 mg/kg), alone and coadministration with carbamazepine (90 mg/kg). Blood samples were collected at an interval of 1, 2, 4, 6, and 8 h, respectively. Glibenclamide concentrations in both in vitro and in vivo samples were estimated by a sensitive RP-HPLC method. The rate of glibenclamide accumulation in the intestine wall of everted sacs was significantly lower after its incubation with carbamazepine when compared to glibenclamide alone treated. In the agreement with the in vivo and in vitro experiments, the presence of carbamazepine induced an enhancement in the concentrations of glibenclamide in plasma and gastrointestinal tract. The results obtained in this study, both under in vivo and in vitro conditions confirm the relevance of P-gp-mediated transport to the intestinal secretion of glibenclamide.

Highlights

P-glycoprotein (P-gp) is a transmembrane protein, associated with a phenotype of multidrug resistance to certain anticancer drugs in mammalian cancer cells, that is able to pump a broad range of structurally and functionally unrelated compounds out of the cell by an ATP-dependent process
The percentage of glibenclamide remain present in ileum are
The plasma glibenclamide levels and pharmacokinetic parameters of glibenclamide such as area under the concentration-time curve (AUC), T1/2, clearance, volume of distribution (Vd), Cmax, and Tmax were altered significantly when comparing the results between GLB alone and combination group (GLB + CAR), and the results are shown in Tables 2, 3, and Figure 3, respectively

Summary

Introduction

P-glycoprotein (P-gp) is a transmembrane protein, associated with a phenotype of multidrug resistance to certain anticancer drugs in mammalian cancer cells, that is able to pump a broad range of structurally and functionally unrelated compounds out of the cell by an ATP-dependent process. New in vitro models have been developed to predict in vivo P-gp activity, in which Caco-2 cell monolayers are widely used to estimate transepithelial passage of different P-gp substrates.[1,2] the correlation between this in vitro model and in vivo studies is rather poor. The use of everted gut sacs has been proposed as a new in vitro model for quantification of P-gp-mediated intestinal efflux for various drugs. This study is planned to evaluate the safety of glibenclamide (an anti-diabetic drug) therapy in the presence of carbamazepine (a prototype drug used to treat painful diabetic neuropathy) in healthy rats. The interaction mechanisms in preclinical studies help to avoid adverse effects when this particular combination was administered to patients suffering with painful diabetic neuropathy

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