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      Transporter-Mediated Drug–Drug Interactions with Oral Antidiabetic Drugs

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          Abstract

          Uptake transporters (e.g., members of the SLC superfamily of solute carriers) and export proteins (e.g., members of the ABC transporter superfamily) are important determinants for the pharmacokinetics of drugs. Alterations of drug transport due to concomitantly administered drugs that interfere with drug transport may alter the kinetics of drug substrates. In vitro and in vivo studies indicate that many drugs used for the treatment of metabolic disorders and cardiovascular diseases (e.g., oral antidiabetic drugs, statins) are substrates for uptake transporters and export proteins expressed in the intestine, the liver and the kidney. Since most patients with type 2 diabetes receive more than one drug, transporter-mediated drug-drug interactions are important molecular mechanisms leading to alterations in oral antidiabetic drug pharmacokinetics with the risk of adverse drug reactions. This review focuses on uptake transporters of the SLCO/SLC21 (OATP) and SLC22 (OCT/OAT) family of solute carriers and export pumps of the ABC (ATP-binding cassette) transporter superfamily (especially P-glycoprotein) as well as the export proteins of the SLC47 (MATE) family and their role for transporter-mediated drug-drug interactions with oral antidiabetic drugs.

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          Most cited references112

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          Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties.

          The organic anion transporting polypeptides (rodents: Oatps, human: OATPs) form a superfamily of sodium-independent transport systems that mediate the transmembrane transport of a wide range of amphipathic endogenous and exogenous organic compounds. Since the traditional SLC21 gene classification does not permit an unequivocal and species-independent identification of genes and gene products, all Oatps/OATPs are newly classified within the OATP/ SLCO superfamily and subdivided into families (>/=40% amino acid sequence identity), subfamilies (>/=60% amino acid sequence identity) and individual genes and gene products according to their phylogenetic relationships and chronology of identification. Implementation of this new classification and nomenclature system occurs in agreement with the HUGO Gene Nomenclature Committee (HGNC). Among 52 members of the OATP/ SLCO superfamily, 36 members have been identified so far in humans, rat and mouse. The latter are clustered within 6 (out of 12) families (OATP1-OATP6) and 13 subfamilies. Oatps/OATPs represent 12 transmembrane domain proteins and contain the superfamily signature D-X-RW-(I,V)-GAWW-X-G-(F,L)-L. Although species divergence, multispecificity and wide tissue distribution are common characteristics of many Oatps/OATPs, some members of the OATP/ SLCO superfamily are highly conserved during evolution, have a high substrate specificity and exhibit unique cellular expression in distinct organs. Hence, while Oatps/OATPs with broad substrate specificity appear to play an important role in the bioavailability, distribution and excretion of numerous exogenous amphipathic organic anionic compounds, Oatps/OATPs with a narrow spectrum of transport substrates may exhibit more specific physiological functions in distinct organs.
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            Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues.

            High expression of the Breast Cancer Resistance Protein (BCRP) gene has been shown to be involved in resistance to chemotherapeutic drugs. Knowledge of the localization of BCRP protein in normal tissues may help unravel the normal function of this protein. Therefore, we characterized the tissue distribution and cellular localization of BCRP in frozen sections of normal human tissues. For this purpose, we used the recently described monoclonal antibody BXP-34 and another independently developed monoclonal antibody directed against BCRP, BXP-21. Both monoclonal antibodies show specific BCRP plasma membrane staining on cytospins obtained from topotecan- or mitoxantrone-selected cell lines, as well as from BCRP-transfected cell lines. Immunoprecipitation experiments using either BXP-21 or BXP-34 yielded a clear M(r) 72,000 BCRP band from BCRP-overexpressing tumor cells. In the topotecan-selected T8 and mitoxantrone-selected MX3 tumor cell lines, BCRP turned out to be differentially glycosylated. In contrast to BXP-34, BXP-21 is able to detect the M(r) 72,000 BCRP protein on immunoblots and is reactive with BCRP in formalin-fixed, paraffin-embedded tissues. Using BXP-21 and BXP-34, prominent staining of BCRP was observed in placental syncytiotrophoblasts, in the epithelium of the small intestine and colon, in the liver canalicular membrane, and in ducts and lobules of the breast. Furthermore, BCRP was present in veinous and capillary endothelium, but not in arterial endothelium in all of the tissues investigated. In the tissues studied, the mRNA levels of BCRP were assessed using reverse transcription-PCR, and these corresponded with the levels of BCRP protein estimated from immunohistochemical staining. The presence of BCRP at the placental syncytiotrophoblasts is consistent with the hypothesis of a protective role of BCRP for the fetus. The apical localization in the epithelium of the small intestine and colon indicates a possible role of BCRP in the regulation of the uptake of p.o. administered BCRP substrates by back-transport of substrate drugs entering from the gut lumen. Therefore, it may be useful to attempt to modulate the uptake of p.o. delivered BCRP substrates, e.g., topotecan or irinotecan, by using a BCRP inhibitor. Clinical trials testing this hypothesis have been initiated in our institute.
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              Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins.

              Multidrug Resistance Proteins (MRPs), together with the cystic fibrosis conductance regulator (CFTR/ABCC7) and the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) comprise the 13 members of the human "C" branch of the ATP binding cassette (ABC) superfamily. All C branch proteins share conserved structural features in their nucleotide binding domains (NBDs) that distinguish them from other ABC proteins. The MRPs can be further divided into two subfamilies "long" (MRP1, -2, -3, -6, and -7) and "short" (MRP4, -5, -8, -9, and -10). The short MRPs have a typical ABC transporter structure with two polytropic membrane spanning domains (MSDs) and two NBDs, while the long MRPs have an additional NH2-terminal MSD. In vitro, the MRPs can collectively confer resistance to natural product drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and, under certain circumstances, alkylating agents. The MRPs are also primary active transporters of other structurally diverse compounds, including glutathione, glucuronide, and sulfate conjugates of a large number of xeno- and endobiotics. In vivo, several MRPs are major contributors to the distribution and elimination of a wide range of both anticancer and non-anticancer drugs and metabolites. In this review, we describe what is known of the structure of the MRPs and the mechanisms by which they recognize and transport their diverse substrates. We also summarize knowledge of their possible physiological functions and evidence that they may be involved in the clinical drug resistance of various forms of cancer.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                Pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                December 2011
                12 October 2011
                : 3
                : 4
                : 680-705
                Affiliations
                Institute of Experimental and Clinical Pharmacology and Toxicology, Clinical Pharmacology and Clinical Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: joerg.koenig@ 123456pharmakologie.med.uni-erlangen.de ; Tel.: +49-9131-8522077; Fax: +49-9131-8522773.
                Article
                pharmaceutics-03-00680
                10.3390/pharmaceutics3040680
                3857053
                24309303
                9685153a-bd11-4475-9ad9-d53fc29e20df
                © 2011 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 11 August 2011
                : 29 August 2011
                : 08 October 2011
                Categories
                Review

                oral antidiabetic drug,organic cation transporter (oct),organic anion transporting polypeptide (oatp),multidrug and toxin extrusion protein (mate),abc (atp-binding cassette) transporter,p-glycoprotein,drug-drug interaction

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