ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin

Clin Pharmacol Ther. 2009 Aug;86(2):197-203. doi: 10.1038/clpt.2009.79. Epub 2009 May 27.

Abstract

The ABCG2 c.421C>A single-nucleotide polymorphism (SNP) was determined in 660 healthy Finnish volunteers, of whom 32 participated in a pharmacokinetic crossover study involving the administration of 20 mg atorvastatin and rosuvastatin. The frequency of the c.421A variant allele was 9.5% (95% confidence interval 8.1-11.3%). Subjects with the c.421AA genotype (n = 4) had a 72% larger mean area under the plasma atorvastatin concentration-time curve from time 0 to infinity (AUC(0-infinity)) than individuals with the c.421CC genotype had (n = 16; P = 0.049). In participants with the c.421AA genotype, the rosuvastatin AUC(0-infinity) was 100% greater than in those with c.421CA (n = 12) and 144% greater than in those with the c.421CC genotype. Also, those with the c.421AA genotype showed peak plasma rosuvastatin concentrations 108% higher than those in the c.421CA genotype group and 131% higher than those in the c.421CC genotype group (P < or = 0.01). In MDCKII-ABCG2 cells, atorvastatin transport was increased in the apical direction as compared with vector control cells (transport ratio 1.9 +/- 0.1 vs. 1.1 +/- 0.1). These results indicate that the ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and, even more so, of rosuvastatin-potentially affecting the efficacy and toxicity of statin therapy.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics*
  • Adult
  • Anticholesteremic Agents / pharmacokinetics
  • Area Under Curve
  • Atorvastatin
  • Cross-Over Studies
  • Drug Resistance, Multiple
  • European Continental Ancestry Group / genetics*
  • Female
  • Finland
  • Fluorobenzenes / administration & dosage
  • Fluorobenzenes / blood
  • Fluorobenzenes / pharmacokinetics*
  • Fluorobenzenes / urine
  • Genotype
  • Heptanoic Acids / administration & dosage
  • Heptanoic Acids / blood
  • Heptanoic Acids / pharmacokinetics*
  • Heptanoic Acids / urine
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics
  • Linear Models
  • Male
  • Neoplasm Proteins / genetics*
  • Polymorphism, Single Nucleotide*
  • Pyrimidines / administration & dosage
  • Pyrimidines / blood
  • Pyrimidines / pharmacokinetics*
  • Pyrimidines / urine
  • Pyrroles / administration & dosage
  • Pyrroles / blood
  • Pyrroles / pharmacokinetics*
  • Pyrroles / urine
  • Reference Values
  • Rosuvastatin Calcium
  • Sulfonamides / administration & dosage
  • Sulfonamides / blood
  • Sulfonamides / pharmacokinetics*
  • Sulfonamides / urine

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Anticholesteremic Agents
  • Fluorobenzenes
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Neoplasm Proteins
  • Pyrimidines
  • Pyrroles
  • Sulfonamides
  • Rosuvastatin Calcium
  • Atorvastatin