Expression, regulation and function of intestinal drug transporters: an update

Abstract

Although oral drug administration is currently the favorable route of administration, intestinal drug absorption is challenged by several highly variable and poorly predictable processes such as gastrointestinal motility, intestinal drug solubility and intestinal metabolism. One further determinant identified and characterized during the last two decades is the intestinal drug transport that is mediated by several transmembrane proteins such as P-gp, BCRP, PEPT1 and OATP2B1. It is well-established that intestinal transporters can affect oral absorption of many drugs in a significant manner either by facilitating their cellular uptake or by pumping them back to gut lumen, which limits their oral bioavailability. Their functional relevance becomes even more apparent in cases of unwanted drug-drug interactions when concomitantly given drugs that cause transporter induction or inhibition, which in turn leads to increased or decreased drug exposure. The longitudinal expression of several intestinal transporters is not homogeneous along the human intestine, which may have functional implications on the preferable site of intestinal drug absorption. Besides the knowledge about the expression of pharmacologically relevant transporters in human intestinal tissue, their exact localization on the apical or basolateral membrane of enterocytes is also of interest but in several cases debatable. Finally, there is obviously a coordinative interplay of intestinal transporters (apical-basolateral), intestinal enzymes and transporters as well as intestinal and hepatic transporters. This review aims to give an updated overview about the expression, localization, regulation and function of clinically relevant transporter proteins in the human intestine.

Protein Kinases C-Mediated Regulations of Drug Transporter Activity, Localization and Expression

“…Various factors, including hormones, cytokines, drugs and environmental contaminants, can modulate expression, localization and/or activity of drug transporters [8,9,10,11,12]. It is important to precisely characterize such regulations, owing notably to the major role played by transporters in pharmacokinetics and some toxic effects of drugs.…”

Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters

“…The intestine is a major absorption site of drugs that are administered via the oral route. Transporters that are present in the enterocytes on the gut wall mucosa govern the initial access into the systemic circulation of molecules such as sugars, amino acids, vitamins, but also of drug substrates . P‐gp, multidrug resistance‐associated protein 2(MRP2), and BCRP, for instance, are major efflux transporters that are responsible for limiting drug absorption.…”

“…OATP1A2 and OATP2B1 have been suggested to participate in the intestinal absorption of drugs in humans . Further, peptide transporter (PEPT)1 is a major uptake transporter that facilitates absorption of peptide‐like drugs in the systemic circulation such as β‐lactam antibiotics . Therefore, drug absorption in children will be highly dependent on the expression and activity of these intestinal transporters.…”

Implication of human drug transporters to toxicokinetics and toxicity of pesticides

“…BCRP shares many substrates with P‐gp, whereas MRP1, MRP2 and MRP3 usually mediate efflux of anionic drugs and drug conjugates . P‐gp and BCRP are notably present at the brush‐border membrane of enterocytes, where they actively expel their substrates in the digestive lumen, thereby preventing or limiting their intestinal absorption . They are also expressed at the luminal pole of brain microvessel endothelial cells and at the apical pole of syncytiotrophoblasts.…”