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
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / genetics*
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Adult
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Anticholesteremic Agents / pharmacokinetics
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Area Under Curve
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Atorvastatin
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Cross-Over Studies
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Drug Resistance, Multiple
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Female
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Finland
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Fluorobenzenes / administration & dosage
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Fluorobenzenes / blood
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Fluorobenzenes / pharmacokinetics*
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Fluorobenzenes / urine
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Genotype
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Heptanoic Acids / administration & dosage
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Heptanoic Acids / blood
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Heptanoic Acids / pharmacokinetics*
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Heptanoic Acids / urine
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics
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Linear Models
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Male
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Neoplasm Proteins / genetics*
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Polymorphism, Single Nucleotide*
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Pyrimidines / administration & dosage
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Pyrimidines / blood
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Pyrimidines / pharmacokinetics*
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Pyrimidines / urine
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Pyrroles / administration & dosage
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Pyrroles / blood
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Pyrroles / pharmacokinetics*
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Pyrroles / urine
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Reference Values
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Rosuvastatin Calcium
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Sulfonamides / administration & dosage
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Sulfonamides / blood
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Sulfonamides / pharmacokinetics*
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Sulfonamides / urine
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White People / genetics*
Substances
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Anticholesteremic Agents
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Fluorobenzenes
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Heptanoic Acids
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Neoplasm Proteins
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Pyrimidines
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Pyrroles
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Sulfonamides
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Rosuvastatin Calcium
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Atorvastatin