Transporter-Mediated Drug-Drug Interactions

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 04/2011; 89(4):481-4. DOI: 10.1038/clpt.2010.359
Source: PubMed


Transporters are membrane-bound proteins that control the access of endogenous and xenobiotics (drugs) to various sites in the human body. They influence drug pharmacokinetics and pharmacodynamics (both benefit and risk) by affecting a drug's absorption, distribution, metabolism (via control of access to metabolizing enzymes), and excretion (ADME) and by controlling drug concentrations at the site of action. Like metabolizing enzymes, transporters have binding sites that are saturable and can be inhibited or induced.

1 Follower
12 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: The absorption of drugs from the gastrointestinal tract is one of the important determinants for oral bioavailability. Development of in vitro experimental techniques such as isolated membrane vesicles and cell culture systems has allowed us to elucidate the transport mechanisms of various drugs across the plasma membrane. Recent introduction of molecular biological techniques resulted in the successful identification of drug transporters responsible for the intestinal absorption of a wide variety of drugs. Each transporter exhibits its own substrate specificity, though it usually shows broad substrate specificity. In this review, we first summarize the recent advances in the characterization of drug transporters in the small intestine, classified into peptide transporters, organic cation transporters and organic anion transporters. In particular, peptide transporter (PEPT1) is the best-characterized drug transporter in the small intestine, and therefore its utilization to improve the oral absorption of poorly absorbed drugs is briefly described. In addition, regulation of the activity and expression levels of drug transporters seems to be an important aspect, because alterations in the functional characteristics and/or expression levels of drug transporters in the small intestine could be responsible for the intra- and interindividual variability of oral bioavailability of drugs. As an example, regulation of the activity and expression of PEPT1 is summarized.
    No preview · Article · Feb 2003 · Drug Metabolism and Pharmacokinetics
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to investigate the influences of various drugs and nutrients on the expression levels of intestinal drug transporters PEPT1, MDR1, MRP2 and MRP3, and drug-metabolizing enzyme CYP3A4. Quantitative reverse transcriptase polymerase chain reaction was used to quantitate transporter and CYP3A4 mRNAs. Western blotting was used to determine protein levels of P-gp. Transport studies of P-gp were performed using cultured Caco-2 cell monolayers. The expression of MDR1 mRNA was increased by all-trans retinoic acid and in glucose-depleted medium, whereas little change of MRP2 and MRP3 mRNA was observed in Caco-2 cells. Substrates and inducers of P-gp or CYP3A4 tended to produce parallel changes in the expression of MDR1 and CYP3A4 mRNA in LS180 cells, whereas in Caco-2 cells no such coordinate response was observed, possibly due to the absence of the expression of steroid xenobiotic receptor (SXR) in this cell line. Several drugs and nutrients were found to affect transporter gene expression level in two human intestinal epithelial cell lines. Since SXR is involved in some expression-regulatory processes, and Caco-2 cells lack SXR, LS180 cells as well as Caco-2 cells should be used for the study of the regulation of intestinal transporters.
    No preview · Article · Sep 2003 · Pharmaceutical Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: A comprehensive list of drug transporters has recently become available as a result of extensive genome analysis, as well as membrane physiology and molecular biology studies. This review covers recent progress in identification and characterization of drug transporters, illustrative cases of successful drug delivery to, or exclusion from, target organs via transporters, and novel experimental approaches to therapeutics using heterologously transduced transporters in tissues. We aim to provide clues that could lead to efficient strategies for the use of transporters to deliver drugs and/or to optimize lead compounds.
    No preview · Article · Sep 2004 · Drug Discovery Today
Show more