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      Role of the Plasma Membrane Transporter of Organic Cations OCT1 and Its Genetic Variants in Modern Liver Pharmacology

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          Abstract

          Changes in the uptake of many drugs by the target cells may dramatically affect the pharmacological response. Thus, downregulation of SLC22A1, which encodes the organic cation transporter type 1 (OCT1), may affect the response of healthy hepatocytes and liver cancer cells to cationic drugs, such as metformin and sorafenib, respectively. Moreover, the overall picture may be modified to a considerable extent by the preexistence or the appearance during the pathogenic process of genetic variants. Some rare OCT1 variants enhance transport activity, whereas other more frequent variants impair protein maturation, plasma membrane targeting or the function of this carrier, hence reducing intracellular active drug concentrations. Here, we review current knowledge of the role of OCT1 in modern liver pharmacology, which includes the use of cationic drugs to treat several diseases, some of them of great clinical relevance such as diabetes and primary liver cancer (cholangiocarcinoma and hepatocellular carcinoma). We conclude that modern pharmacology must consider the individual evaluation of OCT1 expression/function in the healthy liver and in the target tissue, particularly if this is a tumor, in order to predict the lack of response to cationic drugs and to be able to design individualized pharmacological treatments with the highest chances of success.

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          Most cited references 99

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          Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis.

           J Tetrud,  P Ballard,  I Irwin (1983)
          Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.
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            Tyrosine kinase inhibitors - a review on pharmacology, metabolism and side effects.

            Tyrosine kinase inhibitors (TKI) are effective in the targeted treatment of various malignancies. Imatinib was the first to be introduced into clinical oncology, and it was followed by drugs such as gefitinib, erlotinib, sorafenib, sunitinib, and dasatinib. Although they share the same mechanism of action, namely competitive ATP inhibition at the catalytic binding site of tyrosine kinase, they differ from each other in the spectrum of targeted kinases, their pharmacokinetics as well as substance-specific adverse effects. With variations from drug to drug, tyrosine kinase inhibitors cause skin toxicity, including folliculitis, in more than 50% of patients. Among the tyrosine kinase inhibitors that are commercially available as yet, the agents that target EGFR, erlotinib and gefitinib, display the broadest spectrum of adverse effects on skin and hair, including folliculitis, paronychia, facial hair growth, facial erythema, and varying forms of frontal alopecia. In contrast, folliculitis is not common during administration of sorafenib and sunitinib, which target VEGFR, PDGFR, FLT3, and others, whereas both agents have been associated with subungual splinter hemorrhages. Periorbital edema is a common adverse effect of imatinib. Besides the haematological side effects of most of TKIs like anemia, thrombopenia and neutropenia, the most common extra-heamatologic adverse effects are edema, nausea, hypothyroidism, vomiting and diarrhea. Regarding possible long term effects, recently cardiac toxicity with congestive heart failure is under debate in patients receiving imatinib and sunitinib therapy; however, this observation was probably relate to patients selection, although, TKIs overall appear to be a very well tolerated drug class.
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              Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin.

              Metformin, a biguanide, is widely used as an oral hypoglycemic agent for the treatment of type 2 diabetes mellitus. The purpose of the present study was to investigate the role of organic cation transporter 1 (Oct1) in the disposition of metformin. Transfection of rat Oct1 cDNA results in the time-dependent and saturable uptake of metformin by the Chinese hamster ovary cell line with K(m) and V(max) values of 377 microM and 1386 pmol/min/mg of protein, respectively. Buformin and phenformin, two other biguanides, were also transported by rOct1 with a higher affinity than metformin: their K(m) values were 49 and 16 microM, respectively. To investigate the role of Oct1 in the disposition of metformin, the tissue distribution of metformin was determined in Oct1 gene-knockout mice after i.v. administration. Distribution of metformin to the liver in Oct1(-/-) mice was more than 30 times lower than that in Oct1(+/+) mice, and can be accounted for by the extracellular space. Distribution to the small intestine was also decreased in Oct1(-/-) mice, whereas that to the kidney as well as the urinary excretion profile showed only minimal differences. In conclusion, the present findings suggest that Oct1 is responsible for the hepatic uptake as well as playing a role in the intestinal uptake of metformin, whereas the renal distribution and excretion are mainly governed by other transport mechanism(s).
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                Author and article information

                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi Publishing Corporation
                2314-6133
                2314-6141
                2013
                31 July 2013
                : 2013
                Affiliations
                1Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Campus Miguel de Unamuno, E.D. S-09, 37007 Salamanca, Spain
                2Department of Physiology and Pharmacology, University of Salamanca, Campus Miguel de Unamuno, E.D. S-09, 37007 Salamanca, Spain
                3National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Instituto de Salud Carlos III, Sinesio Delgado 4, 28029 Madrid, Spain
                Author notes
                *Jose J. G. Marin: jjgmarin@ 123456usal.es

                Academic Editor: Hongqun Liu

                Article
                10.1155/2013/692071
                3747481
                23984399
                Copyright © 2013 Elisa Lozano et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Review Article

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