ABCG2 Polymorphism Markedly Affects the Pharmacokinetics of Atorvastatin and Rosuvastatin

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–∞ ) than individuals with the c.421CC genotype had ( n = 16; P = 0.049). In participants with the c.421AA genotype, the rosuvastatin AUC 0–∞ 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 ≤ 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. Clinical Pharmacology & Therapeutics (2009); 86 , 2, 197–203 doi: 10.1038/clpt.2009.79