Ethnic variability in the plasma exposures of OATP1B1 substrates such as HMG-CoA reductase inhibitors: a kinetic consideration of its mechanism

Clin Pharmacol Ther. 2013 Jul;94(1):37-51. doi: 10.1038/clpt.2012.221. Epub 2012 Nov 7.

Abstract

Because the plasma exposure levels of rosuvastatin in Asians are generally twice those in Caucasians, the starting dose for Asians in the United States is set to half of that for non-Asians. However, the precise role of ethnicity in the clearance of rosuvastatin has not yet been clarified. This review focuses on ethnic variability in the clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (statins) and angiotensin II receptor antagonists. The mechanisms of such variability are discussed quantitatively, with building a hypothetical model for pravastatin, and validated against other statins. Our analyses suggest that the ethnic variability in the plasma exposure of statins cannot be explained only by the difference in the allele frequencies of organic anion-transporting polypeptide (OATP)1B1 and breast cancer resistance protein (BCRP), and the intrinsic ethnic variability in the activity of OATP1B1 (the ratio of Japanese/Caucasians is 0.584) must be considered. Further work and validation with additional data will clarify the applicability of this model to other OATP1B1 substrates.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • Angiotensin Receptor Antagonists / administration & dosage
  • Angiotensin Receptor Antagonists / pharmacokinetics
  • Biological Availability
  • Biological Transport
  • Dose-Response Relationship, Drug
  • Ethnic Groups / genetics*
  • Fluorobenzenes / administration & dosage
  • Fluorobenzenes / pharmacokinetics*
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics*
  • Liver / metabolism
  • Liver-Specific Organic Anion Transporter 1
  • Neoplasm Proteins / genetics
  • Organic Anion Transporters / genetics*
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacokinetics*
  • Rosuvastatin Calcium
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacokinetics*
  • Tissue Distribution

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Angiotensin Receptor Antagonists
  • Fluorobenzenes
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Liver-Specific Organic Anion Transporter 1
  • Neoplasm Proteins
  • Organic Anion Transporters
  • Pyrimidines
  • SLCO1B1 protein, human
  • Sulfonamides
  • Rosuvastatin Calcium