Clinical relevance of drug efflux pumps in the gut
Introduction
The primary functions of efflux pumps located in the apical membrane of enterocytes are to protect the body against xenobiotics and to facilitate the excretion of endogenous substances such as uric acid [1•]. The efflux pumps eliminate a broad variety of structurally diverse substances including therapeutic drugs directly after absorption into the enterocytes. Therefore, intestinally expressed efflux pumps can be major determinants of the pharmacokinetics, safety and efficacy of drugs [2, 3, 4•]. Induction and inhibition of intestinal efflux pumps are major mechanisms underlying drug–drug interactions in humans [4•].
Important efflux pumps in the small intestine are the ATP-binding cassette (ABC) transporter family members P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2). They are localized in the luminal membrane of enterocytes (Figure 1) and use ATP as an energy source, allowing them to transport substrates against a concentration gradient. Their partially overlapping substrate spectrum, coupled with their cellular colocalization, suggests a concerted function of these three efflux pumps that would comprise a significant barrier to the intestinal absorption of xenobiotics. Absolute protein expression levels of these transporters in the human duodenum have recently been quantified with the rank order BCRP > P-gp ≫ MRP2 [5].
Genes encoding P-gp, BCRP and MRP2 are ABCB1, ABCG2 and ABCC2, respectively. To date, a number of synonymous and nonsynonymous single nucleotide polymorphisms (SNPs) are known in those genes [6, 7, 8]. SNPs relevant for drug disposition or effects in humans will be discussed in the respective paragraphs.
In this article, the role of efflux pumps in the gut for drug disposition and effects is reviewed using selected examples for each transporter. We focus on data obtained in humans. Animal models, in particular transporter-deficient mice, have been very valuable in recognition of the functional importance of intestinal efflux transporters. Therefore, we would like to draw the readers’ attention also to the article by Dr. Schinkel and colleagues on ‘Mouse models for oral drug absorption, disposition and metabolism’ published in the same issue [9].
Section snippets
P-glycoprotein
P-gp (gene: ABCB1) is a protein consisting of two homologous halves, each containing six transmembrane helices and one nuclear-binding domain [10, 11]. The protein expression of P-gp has been shown to increase from proximal to distal parts of the intestine [12, 13]. P-gp generally tends to transport hydrophobic, amphipathic or cationic compounds [14]. Clinically important P-gp substrates include anticancer agents, cardiovascular drugs and immunosuppressants as listed in Table 1 [15]. It is of
Breast cancer resistance protein
BCRP (encoded by the ABCG2 gene) is also localized in the apical membrane of enterocytes (Figure 1). BCRP is a half-size ABC transporter with one nuclear-binding domain and six transmembrane helices, and is believed to function as a homodimer or homotetramer [36]. There is apparently no significant difference in the expression of BCRP from upper to lower small intestine [13], while a considerable, 12-fold interindividual variability in BCRP protein levels has been reported in human duodenum
MRP2
MRP2 consists of two transmembrane domains and two nucleotide-binding domains with an additional N-terminal transmembrane domain consisting of five transmembrane helices [47]. MRP2 expression is regulated by PXR, farnesoid X receptor (FXR) and CAR [48], and it colocalizes with P-gp in the apical membrane of the enterocyte.
MRP2 serves as an efflux pump for some therapeutic drugs as well as anionic drug conjugates (glucuronides, sulfates, glutathiones) and endogenous compounds (Table 1) [14, 47].
Conclusions
Human intestinal P-gp limits bioavailability of drugs and induction and inhibition of intestinal P-gp are important mechanisms underlying drug–drug interactions in humans. Direct evidence for these processes in humans was largely generated using studies in healthy volunteers, who received P-gp drug substrates with negligible drug metabolism such as digoxin and talinolol. Further work is required regarding the importance of intestinal P-gp for drug disposition and drug–drug interactions for the
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Our work on drug transporters is supported by the German Federal Ministry of Education and Research (BMBF, project grant no. 13EX1015B) and the DOKTOR ROBERT PFLEGER-Stiftung Bamberg.
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