Статья

ABCG2 Polymorphism Markedly Affects the Pharmacokinetics of Atorvastatin and Rosuvastatin

Jenni E. KeskitaloDepartment of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, FinlandOliver ZolkInstitute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen–Nuremberg, Erlangen, GermanyMartin F. FrommInstitute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen–Nuremberg, Erlangen, GermanyKJ KurkinenDepartment of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, FinlandPertti J. NeuvonenDepartment of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, FinlandMikko NiemiDepartment of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

2009en

ABI

Аннотация

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.

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Идентификаторы

DOI: 10.1038/clpt.2009.79

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