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Impact of genetic polymorphisms in transmembrane carrier-systems on drug and xenobiotic distribution

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An Erratum to this article was published on 10 December 2003

Abstract

Active transport across biological membranes has become a noticeable factor in the absorption, distribution, and excretion of an increasing number of drugs. Different transmembrane transport systems including organic anion transporters (OATP, solute carrier family SLC21A), organic cation transporters (OCT, SLC22A), dipeptide transporters (PEPT, SLC15A), nucleoside transporters (CNT, SLC28A), monocarboxylate carriers (MCT, SLC2A), and members of the large ATP-binding cassette family (ABC, SLC3A) are involved in drug disposition. Genetic polymorphisms in transport proteins frequently occur and contribute to interindividual differences in the efficacy and safety of pharmatherapy. Currently, the most advanced research has been done on P-glycoprotein (ABCB1, SLC3A1.201.1). Knowledge of this transporter indicates that haplotype analysis rather than association with single nucleotide polymorphisms (SNPs) provides the most appropriate interpretation of pharmacogenetic data from drug transporters. This review gives an overview and update on the pharmacological impact of genetic variants in transmembrane transporters.

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References

  • Arndt P et al (2001) Interaction of cations, anions, and weak base quinine with rat renal cation transporter rOCT2 compared with rOCT1. Am J Physiol Renal Physiol 281:110–115

    Google Scholar 

  • Avdeef A (2001) Physicochemical profiling (solubility, permeability and charge state). Curr Top Med Chem 1:277–351

    CAS  PubMed  Google Scholar 

  • Ayrton A, Morgan P (2001) Role of transport proteins in drug absorption, distribution and excretion. Xenobiotica 31:469–497

    Article  CAS  PubMed  Google Scholar 

  • Borst P, Oude Elferink R (2002) Mammalian ABC transporters in health and disease. Annu Rev Biochem 71:537–592

    Google Scholar 

  • Camenisch G et al (1996) Review of theoretical passive drug absorption models: historical background, recent development and limitations. Pharm Acta Helv 71:309–327

    Article  CAS  PubMed  Google Scholar 

  • Cascorbi I et al (2001) Frequency of single nucleotide polymorphisms (SNPs) in the P-glycoprotein drug transporter MDR1 gene in Caucasians. Clin Pharmacol Ther 69:169–174

    Article  CAS  PubMed  Google Scholar 

  • Cherrington NJ et al (2002) Organ distribution of multidrug resistance proteins 1, 2, and 3 (Mrp1, 2, and 3) mRNA and hepatic induction of Mrp3 by constitutive androstane receptor activators in rats. J Pharmacol Exp Ther 300:97–104

    Article  CAS  PubMed  Google Scholar 

  • Cole SPC et al (1992) Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258:1650–1654

    Google Scholar 

  • Conrad S et al (2001) Identification of human multidrug resistance protein 1 (MRP1) mutations and characterization of a G671 V substitution. J Hum Genet 46:656–663

    Article  CAS  PubMed  Google Scholar 

  • Conrad S et al (2002) A naturally occurring mutation in MRP1 results in a selective decrease in organic anion transport and in increased doxorubicin resistance. Pharmacogenetics 12:321–330

    Article  CAS  PubMed  Google Scholar 

  • Cordon-Cardo C et al (1990) Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 38:1277–1287

    CAS  PubMed  Google Scholar 

  • Covitz KM et al (1998) Membrane topology of the human dipeptide transporter, hPEPT1, determined by epitope insertions. Biochemistry 37:15214–15221

    Article  CAS  PubMed  Google Scholar 

  • Cvetkovic M et al (1999) OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos 27:866–871

    CAS  PubMed  Google Scholar 

  • De Lange EC et al (1998) BBB transport and P-glycoprotein functionality using MDR1A (-/-) and wild-type mice. Total brain versus microdialysis concentration profiles of rhodamine-123. Pharm Res 15:1657–1665

    Article  PubMed  Google Scholar 

  • Dresser MJ et al (2001) Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J Pharm Sci 90:397–421

    CAS  PubMed  Google Scholar 

  • Fei YJ et al (1997) Identification of the histidyl residue obligatory for the catalytic activity of the human H+/peptide cotransporters PEPT1 and PEPT2. Biochemistry 36:452–460

    Article  CAS  PubMed  Google Scholar 

  • Fellay J et al (2002) Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 359:30–36

    Article  CAS  PubMed  Google Scholar 

  • [76] Fromm M (2002) The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans. Adv Drug Deliv Rev 54:1295–1310

    Article  PubMed  Google Scholar 

  • Ganapathy ME et al (1995) Differential recognition of beta-lactam antibiotics by intestinal and renal peptide transporters, PEPT 1 and PEPT 2. J Biol Chem 270:25672–25677

    Article  CAS  PubMed  Google Scholar 

  • Ganapathy V, Leibach FH (1986) Carrier mediated reabsorption of small peptides in renal proximal tubule. Am J Physiol 251:F945–F953

    CAS  PubMed  Google Scholar 

  • Gao M et al (1998) Multidrug resistance protein. J Biol Chem 273:10733–10740

    Article  CAS  PubMed  Google Scholar 

  • Gerloff T et al (2002) MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males. Br J Clin Pharmacol 54:610–616

    Article  CAS  PubMed  Google Scholar 

  • Gorboulev V et al (1997) Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 16:871–881

    CAS  PubMed  Google Scholar 

  • Greiner B et al (1999) The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 104:147–153

    CAS  PubMed  Google Scholar 

  • Gründemann D et al (1994) Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372:549–552

    PubMed  Google Scholar 

  • Hagenbuch B, Meier PJ (2003) The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 1609:1–18

    Article  CAS  PubMed  Google Scholar 

  • Han H et al (1998) 5’-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter. Pharm Res 15:1154–1159

    Article  CAS  PubMed  Google Scholar 

  • Hidalgo IJ et al (1995) Structural requirements for interaction with the oligopeptide transporter in Caco-2 cells. Pharm Res 12:317–319

    Article  CAS  PubMed  Google Scholar 

  • Higgins CF (2001) ABC transporters: physiology, structure and mechanism—an overview. Res Microbiol 152:205–210

    Article  CAS  PubMed  Google Scholar 

  • Hipfner DR et al (1999) Monoclonal antibodies that inhibit the transport function of the 190-kDa multidrug resistance protein, MRP. J Biol Chem 274:15420–15426

    Article  CAS  PubMed  Google Scholar 

  • Hitzl M et al (2001) The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells. Pharmacogenetics 11:1–6

    PubMed  Google Scholar 

  • Hoffmeyer S et al (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478

    CAS  PubMed  Google Scholar 

  • Hsiang B et al (1999) A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem 274:37161–37168

    Article  CAS  PubMed  Google Scholar 

  • Hu M et al (1995) Mechanisms of transport of quinapril in Caco-2 cell monolayers: comparison with cephalexin. Pharm Res 12:1120–1125

    Article  CAS  PubMed  Google Scholar 

  • Iida A et al (2001) Catalog of 258 single-nucleotide polymorphisms (SNPs) in genes encoding three organic anion transporters, three organic anion transporting polypeptide, and three NADH:ubiquinone oxidoreductase flavoproteins. J Hum Genet 46:668–683

    Google Scholar 

  • Ishizuka H et al (1998) Transport of temocaprilat into rat hepatocytes: role of organic anion transporting polypeptide. J Pharmacol Exp Ther 287:37–42

    Google Scholar 

  • Ito S et al (2001) Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics 11:175–184

    Google Scholar 

  • Itoda M et al (2002) Polymorphisms in the ABCC2 (cMOAT/MRP2) gene found in 72 established cell lines derived from Japanese individuals: an association between single nucleotide polymorphisms in the 5’-untranslated region and exon 28. Drug Metab Dispos 30:363–364

    Article  CAS  PubMed  Google Scholar 

  • Johne A et al (2002) Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther 72:584–594

    Article  CAS  PubMed  Google Scholar 

  • Juranka PF et al (1989) P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins. FASEB J 3:2583–2592

    CAS  PubMed  Google Scholar 

  • Keppler D et al (1997) Transport of glutathione conjugates and glucuronides by the multidrug resistance proteins MRP1 and MRP2. Biol Chem 378:787–791

    CAS  PubMed  Google Scholar 

  • [77] Kerb R et al (2001) ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2. Pharmacogenomics 2:51–64

    CAS  PubMed  Google Scholar 

  • Kerb R et al (2002) Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics 12:591–595

    Google Scholar 

  • Kim RB et al (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199

    Google Scholar 

  • Konig J et al (1999) Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta 1461:377–394

    PubMed  Google Scholar 

  • Koepsell H (1998) Organic cation transporters in intestine, kidney, liver, and brain. Annu Rev Physiol 60:243–266

    CAS  PubMed  Google Scholar 

  • Kruijtzer CM et al (2002) Improvement of oral drug treatment by temporary inhibition of drug transporters and/or cytochrome P450 in the gastrointestinal tract and liver: an overview. Oncologist 7:516–530

    CAS  PubMed  Google Scholar 

  • Kullak-Ublick GA et al (2001) Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 120:525–533

    Google Scholar 

  • Lazar et al (2003) Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3). J Hum Genet 48:226–230

    CAS  PubMed  Google Scholar 

  • Leabman MK et al (2002) Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics 12:395–405

    Google Scholar 

  • Lee VHL (2000) Membrane transporters. Eur J Pharm Sci 11:S41–S50

    CAS  PubMed  Google Scholar 

  • Meier PJ et al (1997) Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver. Hepatology 26:1667–1677

    CAS  PubMed  Google Scholar 

  • Michalski C et al (2002) A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter. J Biol Chem 277:43058–43063

    Article  CAS  PubMed  Google Scholar 

  • Muller M (2001) 48 human ATP-binding cassette transporters. http://www.nutrigene.4t.com/humanabc.htm

  • Nishizato Y et al (2003) Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 73:554–565

    Article  CAS  PubMed  Google Scholar 

  • Nozawa T et al (2002) Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allelic frequencies in the Japanese population and functional analysis. J Pharmacol Exp Ther 302:804–813

    Article  CAS  PubMed  Google Scholar 

  • Palm K et al (1996) Correlation of drug absorption with molecular surface properties. J Pharm Sci 85:32–39

    Article  CAS  PubMed  Google Scholar 

  • Pang KS et al (1998) The modified dipeptide, enalapril, an angiotensin-converting enzyme inhibitor, is transported by the rat liver organic anion transport protein. Hepatology 28:1341–1346

    CAS  PubMed  Google Scholar 

  • Pauli-Magnus C et al (2002) No effect of MDR1 C3435T polymorphism on disposition and CNS effects of loperamide [abstract]. Clin Pharmacol Ther 71:P72

    Google Scholar 

  • Paulusma CC, Oude Elferink RP (1997) The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man. J Mol Med 75:420–428

    Article  CAS  PubMed  Google Scholar 

  • Rao VV et al (1999) Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci USA 96:3900–3905

    Article  CAS  PubMed  Google Scholar 

  • Saito H et al (1997) Cloning and characterization of a pH-sensing regulatory factor that modulates transport activity of the human H+/peptide cotransporter, PEPT1. Biochem Biophys Res Commun 237:577–582

    Article  CAS  PubMed  Google Scholar 

  • Sakaeda T et al (2001) MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res 18:1400–1404

    Article  CAS  PubMed  Google Scholar 

  • Schaub TP et al (1997) Expression of the conjugate export pump encoded by the mrp2 gene in the apical membrane of kidney proximal tubules. J Am Soc Nephrol 8:1213–1221

    CAS  PubMed  Google Scholar 

  • Sellin JH (1996) The pathophysiology of diarrhea. In: Schultz SG, Adndreoli TE, Brown AM, Fambrough DM, Hoffman JF, Welsh MJ (eds) Molecular biology of membrane transport disorders. Plenum, New York, pp 541–563

  • Siegmund W et al (2002) The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Clin Pharmacol Ther 72:572–583

    Article  CAS  PubMed  Google Scholar 

  • Stenberg P et al (2000) Virtual screening of intestinal drug permeability. J Control Release 65:231–243

    Article  CAS  PubMed  Google Scholar 

  • Tamai I et al (2000) Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem Biophys Res Commun 273:251–260

    Article  CAS  PubMed  Google Scholar 

  • Tanigawara Y (2000) Role of P-glycoprotein in drug disposition. Ther Drug Monit 22:137–140

    Article  CAS  PubMed  Google Scholar 

  • Temple CS, Boyd CA (1998) Proton-coupled oligopeptide transport by rat renal cortical brush border membrane vesicles: a functional analysis using ACE inhibitors to determine the isoform of the transporter. Biochim Biophys Acta 1373:277–281

    Article  CAS  PubMed  Google Scholar 

  • Terada T et al (1996) Identification of the histidine residues involved in substrate recognition by a rat H+/peptide cotransporter, PEPT1. FEBS Lett 394:196–200

    Article  CAS  PubMed  Google Scholar 

  • Tirona RG et al (2001) Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem 276:35669–35675

    Article  CAS  PubMed  Google Scholar 

  • Urtti A et al (2001) Genomic structure of proton-coupled oligopeptide transporter hPEPT1 and pH sensing regulatory splice variant. AAPS Pharm Sci 3:E6

    Article  CAS  Google Scholar 

  • Van Aubel RA et al (2000) Expression and immunolocalization of multidrug resistance protein 2 in rabbit small intestine. Eur J Pharmacol 400:195–198

    Article  PubMed  Google Scholar 

  • Van Montfoort JE et al (2001) Comparison of ‘type I’ and ‘type II’ organic cation transport by organic cation transporters and organic anion-transporting polypeptides. J Pharmacol Exp Ther 298:110–115

    PubMed  Google Scholar 

  • Wacher VJ et al (1995) Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 13:129–134

    CAS  PubMed  Google Scholar 

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  1. Institute of Clinical Pharmacology, Charité University Medical Center, Humboldt University, Schumannstrasse 20/21, 10098, Berlin, Germany

    Thomas Gerloff

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Correspondence to Thomas Gerloff.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00210-003-0856-7

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Gerloff, T. Impact of genetic polymorphisms in transmembrane carrier-systems on drug and xenobiotic distribution. Naunyn-Schmiedeberg's Arch Pharmacol 369, 69–77 (2004). https://doi.org/10.1007/s00210-003-0813-5

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