Impact of drug transporter pharmacogenomics on pharmacokinetic and pharmacodynamic variability - considerations for drug development

Expert Opin Drug Metab Toxicol. 2012 Jun;8(6):723-43. doi: 10.1517/17425255.2012.678048. Epub 2012 Apr 18.


Introduction: Drug transporter proteins are expressed on the cell membrane, regulating substrate exposure in systemic circulation and/or peripheral tissues. Genetic polymorphism of drug transporter genes encoding these proteins could alter the functional activity and/or protein expression, having effects on absorption, distribution, metabolism and excretion (ADME), efficacy and adverse effects.

Areas covered: The authors provide the reader with an overview of the pharmacogenetics (PGx) of 12 membrane transporters. The clinical literature is summarized as to the quantitative significance on pharmacokinetics (PK) and implications on pharmacodynamics (PD) and adverse effects, due to transporter influence on intracellular drug concentrations.

Expert opinion: Unlike polymorphisms for cytochrome P450s (CYPs) resulting in large magnitude of PK variation, genetic mutations for membrane transporters are typically less than threefold alteration in systemic PK for drugs with a few exceptions. However, substantially greater changes in intracellular drug levels may result. We are aware of 1880 exome variants in 12 of the best-studied transporters to date, and nearly 40% of these change the amino acid. However, the functional consequences of most of these variants remain to be determined, and have only been empirically evaluated for a handful. To the extent that genetic polymorphisms impact ADME, it is a variable that will contribute to ethnic differences due to substantial frequency differences for the known variants.

Publication types

  • Review

MeSH terms

  • Animals
  • Cell Membrane Permeability
  • Drug Discovery*
  • Drug Interactions
  • Drug-Related Side Effects and Adverse Reactions
  • Genotype
  • Humans
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Mutation
  • Pharmaceutical Preparations / metabolism*
  • Pharmacogenetics*
  • Pharmacokinetics*
  • Phenotype
  • Polymorphism, Genetic


  • Membrane Transport Proteins
  • Pharmaceutical Preparations