title: Polymorphisms of the drug transporters ABCB1, ABCG2, ABCC2 and ABCC3 and their impact on drug bioavailability and clinical relevance.
abstract: BACKGROUND
  Human ATP-binding cassette (ABC) transporters act as translocators of numerous substrates across extracellular and intracellular membranes, thereby contributing to bioavailability and consequently therapy response. Genetic polymorphisms are considered as critical determinants of expression level or activity and subsequently response to selected drugs.
  
  
  METHODS
  Here the influence of polymorphisms of the prominent ABC transporters P-glycoprotein (MDR1, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and the multidrug resistance-associated protein (MRP) 2 (ABCC2) as well as MRP3 (ABCC3) on the pharmacokinetic of drugs and associated consequences on therapy response and clinical outcome is discussed.
  
  
  CONCLUSIONS
  ABC transporter genetic variants were assumed to affect interindividual differences in pharmacokinetics and subsequently clinical response. However, decades of medical research have not yielded in distinct and unconfined reproducible outcomes. Despite some unique results, the majority were inconsistent and dependent on the analyzed cohort or study design. Therefore, variability of bioavailability and drug response may be attributed only by a small amount to polymorphisms in transporter genes, whereas transcriptional regulation or post-transcriptional modification seems to be more critical. In our opinion, currently identified genetic variants of ABC efflux transporters can give some hints on the role of transporters at interfaces but are less suitable as biomarkers to predict therapeutic outcome.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein , Campus Kiel, Arnold-Heller-Str. 3, 24105 Kiel , Germany +49 431 597 3500 ; +49 431 597 3522 ; cascorbi@pharmakologie.uni-kiel.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bruhn
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D015415:Biomarkers / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C114462:multidrug resistance-associated protein 3
keywords: ATP-binding cassette transporters; drug response; efflux transporter; multidrug resistance; pharmacogenetics; pharmacokinetics; transmembranal transport