ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development

Curr Pharm Des. 2014;20(5):793-807. doi: 10.2174/138161282005140214165212.


Multidrug resistance (MDR) is a serious problem that hampers the success of cancer pharmacotherapy. A common mechanism is the overexpression of ATP-binding cassette (ABC) efflux transporters in cancer cells such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2) that limit the exposure to anticancer drugs. One way to overcome MDR is to develop ABC efflux transporter inhibitors to sensitize cancer cells to chemotherapeutic drugs. The complete clinical trials thus far have showen that those tested chemosensitizers only add limited or no benefits to cancer patients. Some MDR modulators are merely toxic, and others induce unwanted drug-drug interactions. Actually, many ABC transporters are also expressed abundantly in the gastrointestinal tract, liver, kidney, brain and other normal tissues, and they largely determine drug absorption, distribution and excretion, and affect the overall pharmacokinetic properties of drugs in humans. In addition, ABC transporters such as P-gp, MRP1 and BCRP co-expressed in tumors show a broad and overlapped specificity for substrates and MDR modulators. Thus reliable preclinical assays and models are required for the assessment of transporter-mediated flux and potential effects on pharmacokinetics in drug development. In this review, we provide an overview of the role of ABC efflux transporters in MDR and pharmacokinetics. Preclinical assays for the assessment of drug transport and development of MDR modulators are also discussed.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / chemistry
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biological Transport / drug effects
  • Drug Design*
  • Drug Evaluation, Preclinical / methods
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Humans
  • Membrane Transport Modulators / chemistry
  • Membrane Transport Modulators / pharmacokinetics*
  • Membrane Transport Modulators / pharmacology
  • Membrane Transport Modulators / therapeutic use
  • Models, Biological*
  • Molecular Conformation
  • Molecular Targeted Therapy
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / metabolism


  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Membrane Transport Modulators
  • Neoplasm Proteins