Impact of ABCG2 and SLCO1B1 polymorphisms on pharmacokinetics of rosuvastatin, atorvastatin and simvastatin acid in Caucasian and Asian subjects: a class effect?

Eur J Clin Pharmacol. 2015 Mar;71(3):341-55. doi: 10.1007/s00228-014-1801-z. Epub 2015 Feb 12.

Abstract

Purpose: Systemic exposure to rosuvastatin is approximately double that of Caucasians in Asian subjects. We investigated whether this pattern of increased exposure exists for other statins.

Methods: Plasma exposure following single-dose rosuvastatin 20 mg, atorvastatin 40 mg or simvastatin 40 mg was studied in Chinese, Japanese and Caucasian subjects. Plasma concentrations were determined using LC-MS methods. Impact of polymorphisms in SLCO1B1 (T521>C and A388>G) and in ABCG2 (C421>A) on exposure to rosuvastatin, atorvastatin, simvastatin and simvastatin acid was assessed.

Results: Relative to Caucasians, geometric mean area under the curve from time zero to time of last quantifiable concentration was 86 % (90 % confidence interval (CI), 51-130 %) and 55 % (26-91 %) higher for rosuvastatin in Chinese and Japanese subjects, respectively, 53 % (25-88 %) and 69 % (37-108 %) higher for atorvastatin, 23 % (0-52 %) and 12 % (-0.9-39 %) higher for simvastatin and 28 % (5-56 %) and 34 % (10-64 %) higher for simvastatin acid. Geometric mean maximum drug concentration was also proportionally higher for each statin. Polymorphisms in SLCO1B1 T521>C or ABCG2 C421>A were associated with higher exposure to rosuvastatin, atorvastatin and simvastatin acid (but not simvastatin) within a population, but only the ABCG2 C421>A polymorphism contributed towards between-population exposure differences. In individuals carrying wild-type alleles for both SLCO1B1 and ABCG2, area under the plasma concentration-time curve (AUC) still appeared to be higher for rosuvastatin, atorvastatin and simvastatin acid in Chinese and Japanese subjects compared with Caucasians, respectively.

Conclusion: Increased exposure to statins in Asian subjects versus Caucasians may represent a more general class phenomenon than previously recognized.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics*
  • Adolescent
  • Adult
  • Aged
  • Asian Continental Ancestry Group / genetics*
  • Atorvastatin / adverse effects
  • Atorvastatin / blood
  • Atorvastatin / pharmacokinetics*
  • European Continental Ancestry Group / genetics*
  • Female
  • Genotype
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / blood
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics
  • Liver-Specific Organic Anion Transporter 1
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Organic Anion Transporters / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Rosuvastatin Calcium / adverse effects
  • Rosuvastatin Calcium / blood
  • Rosuvastatin Calcium / pharmacokinetics*
  • Simvastatin / adverse effects
  • Simvastatin / analogs & derivatives*
  • Simvastatin / blood
  • Simvastatin / pharmacokinetics*
  • Young Adult

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Liver-Specific Organic Anion Transporter 1
  • Neoplasm Proteins
  • Organic Anion Transporters
  • SLCO1B1 protein, human
  • Rosuvastatin Calcium
  • simvastatin acid
  • Atorvastatin
  • Simvastatin