Possible Role of P-Glycoprotein in Cyclosporine -Acitretin Drug Interaction

Subhashri Shrihari Rajendran,Vimalavathini Ramesh

doi:10.24018/ejmed.2019.1.4.62

Subhashri Shrihari Rajendran, Vimalavathini Ramesh

Open Access

https://doi.org/10.24018/ejmed.2019.1.4.62

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Abstract

P-glycoprotein, an efflux transporter prevents intracellular accumulation of xenobiotics. Cyclosporine A and acitretin are used to treat psoriasis. The present research work aims to investigate the possible role of P-glycoprotein in Cyclosporine- Acitretin drug interaction due to evidence of both drugs having affinity for P-glycoprotein.The study has three different objective namely to assess apparent permeability coefficient of cyclosporine in presence of acitretin by non-everted sac technique, to study the intestinal permeation and absorption kinetics of cyclosporine in presence of acitretin by single pass intestinal perfusion (SPIP) technique and to study the influence of acitretin on oral bioavailability of cyclosporine in Wistar rats.The result of ex vivo, in situ and in vivo study showed that cyclosporine level increased in a time dependent manner. As the dose of acitretin increases the cyclosporine concentration in all three methods tend to increase and was statistically significant. The improvement in absorption of cyclosporine may be due to the inhibition of P-glycoprotein transporter in the intestine by acitretin. Thus acitretin may enhance the oral pharmacokinetics of cyclosporine. Hence this combination may require close monitoring for better therapeutic outcome. Our study confirmed the inhibitory role of acitretin on P-glycoprotein leading to increase concentration of cyclosporine.

Highlights

Drug transporters and metabolizing enzymes play vital role in determining the pharmacological action of drugs
Cyclosporine is a substrate of pharmacological action of drugs. Pglycoprotein (P-gp) and in silico and in vitro cell culture studies show that acitretin has affinity for Pgp [6]
We hypothesize possible drug interaction between these two drugs mediated by P-gp which may affect the effectiveness of this combination therapy

Summary

INTRODUCTION

Drug transporters and metabolizing enzymes play vital role in determining the pharmacological action of drugs. Pglycoprotein (P-gp) is an active, efflux, membrane bound transport protein pump encoded by multi-drug resistance (MDR1) gene, known as ABCB1 gene in humans [1]. P-gp due to genetic polymorphism may affect drug therapy in two ways first, it increases the expression of P-gp thereby it reduces the bioavailability and leads to therapeutic failure and secondly, it decreases P-gp expression and thereby produces drug toxicity [3]. It is highly expressed in cancer cells, leading to efflux of anticancer agents from cells which confer chemotherapeutic drug resistance [4]. The study has three different objective namely to assess apparent permeability coefficient of cyclosporine in presence of acitretin using Wistar rats by non-everted sac technique, to study the intestinal permeation and absorption kinetics of cyclosporine in presence of acitretin using Wistar rats by single pass intestinal perfusion (SPIP) study and to study the influence of acitretin on oral bioavailability of cyclosporine in Wistar rat

MATERIALS AND METHODS

Effect of acitretin on oral bioavailability of cyclosporine

STATISTICAL ANALYSIS

Ex-vivo

In situ: single pass intestinal perfusion technique

Discussion