Intestinal drug transporters: An overview

Abstract

The importance of drug transporters as one of the determinants of pharmacokinetics has become increasingly evident [1]. While much research has been conducted focusing the role of drug transporters in the liver [2], [3], [4], [5] and kidney [2], [6], [7] less is known about the importance of uptake and efflux transporters identified in the intestine [8]. Over the past years the effects of intestinal transporters have been studied using in vivo models, in situ organ perfusions, in vitro tissue preparations and cell lines. This review aims to describe up to date findings regarding the importance of intestinal transporters on drug absorption and bioavailability, highlighting areas in need of further research. Wu and Benet [9] proposed a Biopharmaceutics Drug Disposition Classification System (BDDCS) that allows the prediction of transporter effects on the drug disposition of orally administered drugs. This review also discusses BDDCS predictions with respect to the role of intestinal transporters and intestinal transporter-metabolizing enzyme interplay on oral drug pharmacokinetics.

Introduction

Membrane transporters can be major determinants of the pharmacokinetics, safety and efficacy profiles of drugs [1]. Transporters are the gatekeepers for cells and organelles, controlling uptake and efflux of crucial compounds such as sugars, amino acids, nucleotides, inorganic ions and drugs [10]. Specific membrane transporters are expressed in the luminal and/or basolateral membranes of enterocytes, hepatocytes, renal tubular epithelial cells and other important barrier tissues, including the blood–brain barrier, blood–testis barrier and the placental barrier [11]. Transporter expression in the intestine and/or liver, the two major sites affecting how much of a drug will get into the systemic circulation after an oral dose, suggests that factors affecting their function will be important determinants of oral drug pharmacokinetics. Regulatory elements controlling protein levels, genetic polymorphisms leading to increased or reduced function and coadministration with inhibitors are all important avenues by which a transporter's ability to transport substrates is altered [12]. While much research has been conducted focusing on the role of drug transporters in the liver [2], [3], [4], [5] and kidney [2], [6], [7] less emphasis has been placed on the importance of uptake and efflux transporters identified in the intestine [8]. In this review we will focus on the role of uptake and efflux transporters identified in the apical and basolateral membranes of the enterocytes with respect to substrate and inhibitor interactions. Detailed characterization, pharmacogenetics and mechanisms of transport can be found in several reviews [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23].