Review
The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability

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Abstract

Many orally administered drugs must overcome several barriers before reaching their target site. The first major obstacle to cross is the intestinal epithelium. Although lipophilic compounds may readily diffuse across the apical plasma membrane, their subsequent passage across the basolateral membrane and into blood is by no means guaranteed. Efflux proteins located at the apical membrane, which include P-glycoprotein (Pgp; MDR1) and MRP2, may drive compounds from inside the cell back into the intestinal lumen, preventing their absorption into blood. Drugs may also be modified by intracellular phase I and phase II metabolising enzymes. This process may not only render the drug ineffective, but it may also produce metabolites that are themselves substrates for Pgp and/or MRP2. Drugs that reach the blood are then passed to the liver, where they are subject to further metabolism and biliary excretion, often by a similar system of ATP-binding cassette (ABC) transporters and enzymes to that present in the intestine. Thus a synergistic relationship exists between intestinal drug metabolising enzymes and apical efflux transporters, a partnership that proves to be a critical determinant of oral bioavailability. The effectiveness of this system is optimised through dynamic regulation of transporter and enzyme expression; tissues have a remarkable capacity to regulate the amounts of protein both at transcriptional and post-transcriptional levels in order to maintain homeostasis. This review addresses the progress to date on what is known about the role and regulation of drug efflux mechanisms in the intestine and liver.

Introduction

The efficacy of many drugs depends critically on their ability to cross cellular barriers to reach their target. Lipophilic drugs may cross these barriers in the absence of specialised transport systems, since these compounds diffuse freely across the plasma membrane. Hydrophilic and charged compounds on the other hand often require specific transport mechanisms to facilitate cellular uptake and/or transcellular transport. However, the extent to which a drug accumulates within a tissue is frequently limited not so much by its ability to enter cells but by its tendency to leave. This may arise from active efflux mechanisms present in the plasma membrane. These efflux mechanisms play a critical role in limiting the absorption and accumulation of potentially toxic substances and can effectively confer resistance to a diverse range of compounds in tumour cells. In the mid-seventies, Juliano and Ling (1976) reported the over-expression of a membrane protein in colchicine-resistant Chinese hamster ovary cells conferred resistance to a wide range of amphiphilic drugs. Since that seminal discovery, this P-glycoprotein (Pgp), an ATP-dependent efflux protein, has been the focus of intense study. Pgp was just the first member of what is now a large and diverse superfamily comprising around fifty human ATP-binding cassette (ABC) proteins that perform many and varied functions (Klein et al., 1999, Muller, 2001). Of particular interest in this review are the family members that mediate drug transport, since these proteins can have a major impact on drug disposition and drug resistance to chemotherapy, as well as physiological homeostasis. These drug efflux proteins principally comprise the MDR (multidrug resistance)- and MRP (multidrug resistance-associated protein)-type transporters. Although these transporters tend to be over-expressed in tumours, their expression is widespread throughout many normal tissues, perhaps most notably in excretory sites such as the liver, kidney, and intestine, where they provide a formidable barrier against drug penetration, while providing a mechanism for drug elimination. The arsenal of ABC transporters that mediate drug efflux is supported by drug metabolising enzymes, which modify drugs to yield metabolites that are themselves substrates for these transporters. Thus, a synergistic relationship exists within excretory tissues to protect the body against invasion by foreign compounds. Although ABC transporters are differentially expressed at certain sites in the body, their expression is by no means static; tissues have a remarkable capacity to regulate the amounts of membrane transporters both at transcriptional and post-transcriptional levels in order to achieve homeostasis.

This review provides insight into the mechanisms that mediate drug efflux in tissues important in determining drug disposition, focusing principally on the intestine and liver. Emphasis is also placed upon the regulation of transporter expression and function, since this is a key component of the body’s adaptive response in maintaining homeostasis.

Section snippets

Efflux mechanisms as barriers to intestinal absorption

The small intestine represents the principal site of absorption for any ingested compound, whether dietary, therapeutic, or toxic. Oral administration is the most popular route for drug administration since dosing is convenient and non-invasive and many drugs are well absorbed by the gastrointestinal tract. As well as degrading and absorbing nutrients and solutes from the intestinal lumen, intestinal enterocytes form a selective barrier to drugs and xenobiotics. This barrier function depends

Family members

Pgp is a member of the human ABC (Higgins, 1992) superfamily, a large group of proteins comprised of membrane transporters, ion channels, and receptors. These proteins show general sequence and structural homology, and on this basis are further divided into subfamilies. ABC transporters are also conserved between species, and many orthologues of the human proteins have been identified and characterised in other mammals, most notably rodents. ABC transporters are by no means restricted to higher

Overview

The previous sections summarised the how, where, and what, of drug transport by ABC efflux proteins. However, this system is highly adaptive; ABC transporters respond to appropriate influences by up- or down-regulation of expression. This observation should come as little surprise since in many cases it was the over-expression of these proteins in multidrug resistant cells that led to their initial discovery. As well as induction by drugs, there is a substantial body of evidence to show that

Inter-individual variations: polymorphisms in ABC genes

Inter-individual variation in drug disposition may be attributed to many factors, including gender, race, genetics, diet, disease state, and concurrent medications. Large inter-individual differences in Pgp and MRP2 expression in tissues such as the small intestine (Fromm et al., 2000, Lown et al., 1997) and liver (Schuetz et al., 1995, Zollner et al., 2001) have also been reported. Additionally, several single nucleotide polymorphisms (SNPs) of the human MDR1 and MRP2 gene have been identified

Future perspectives

ABC efflux transporters can have a profound effect on oral drug bioavailability. These effects may be augmented by intracellular metabolising enzymes, which not only modify compounds, but also form a molecular tag-team with efflux proteins by producing metabolites that are themselves substrates for ABC transporters. If the bioavailability of such compounds is to be improved, then ways to overcome drug elimination via these mechanisms must be found. In clinical studies, Pgp has been targeted by

Acknowledgements

The authors wish to thank Dr. David S. Miller (NIEHS, Research Triangle Park, NC) and Dr. Dianne Ford (University of Newcastle) for their critical evaluation of the manuscript. LMSC and SL acknowledge the support of BBSRC, co-funded by AstraZeneca (LMSC) and GlaxoSmithKline (SL), for their studies at Newcastle Medical School and SL gratefully acknowledges the support of Prof. Nicholas L. Simmons during this time.

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