Genetics or environment in drug transport: the case of organic anion transporting polypeptides and adverse drug reactions

Expert Opin Drug Metab Toxicol. 2012 Mar;8(3):349-60. doi: 10.1517/17425255.2012.656087. Epub 2012 Jan 27.

Abstract

Introduction: Organic anion transporting polypeptide (OATP) uptake transporters are important for the disposition of many drugs and perturbed OATP activity can contribute to adverse drug reactions (ADRs). It is well documented that both genetic and environmental factors can alter OATP expression and activity. Genetic factors include single nucleotide polymorphisms (SNPs) that change OATP activity and epigenetic regulation that modify OATP expression levels. SNPs in OATPs contribute to ADRs. Environmental factors include the pharmacological context of drug-drug interactions and the physiological context of liver diseases. Liver diseases such as non-alcoholic fatty liver disease, cholestasis and hepatocellular carcinoma change the expression of multiple OATP isoforms. The role of liver diseases in the occurrence of ADRs is unknown.

Areas covered: This article covers the roles OATPs play in ADRs when considered in the context of genetic or environmental factors. The reader will gain a greater appreciation for the current evidence regarding the salience and importance of each factor in OATP-mediated ADRs.

Expert opinion: A SNP in a single OATP transporter can cause changes in drug pharmacokinetics and contribute to ADRs but, because of overlap in substrate specificities, there is potential for compensatory transport by other OATP isoforms. By contrast, the expression of multiple OATP isoforms is decreased in liver diseases, reducing compensatory transport and thereby increasing the probability of ADRs. To date, most research has focused on the genetic factors in OATP-mediated ADRs while the impact of environmental factors has largely been ignored.

Publication types

  • Review

MeSH terms

  • Animals
  • Biological Transport
  • Drug Interactions
  • Drug-Related Side Effects and Adverse Reactions*
  • Environment*
  • Genetic Predisposition to Disease
  • Humans
  • Liver Diseases / complications
  • Liver Diseases / metabolism
  • Organic Cation Transport Proteins / chemistry
  • Organic Cation Transport Proteins / genetics*
  • Organic Cation Transport Proteins / metabolism
  • Pharmaceutical Preparations / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Protein Conformation
  • Risk Assessment
  • Risk Factors
  • Structure-Activity Relationship

Substances

  • Organic Cation Transport Proteins
  • Pharmaceutical Preparations