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

• Published in: European journal of clinical pharmacology Vol. 71; no. 3; pp. 341 - 355
• Main Authors: Birmingham, Bruce K., Bujac, Sarah R., Elsby, Robert, Azumaya, Connie T., Wei, Cheryl, Chen, Yusong, Mosqueda-Garcia, Rogelio, Ambrose, Helen J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2015; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Asian Continental Ancestry Group - genetics; Asian people; Atorvastatin Calcium - adverse effects; Atorvastatin Calcium - blood; Atorvastatin Calcium - pharmacokinetics; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; Biomedical and Life Sciences; Biomedicine; European Continental Ancestry Group - genetics; Female; Genotype; Genotype & phenotype; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Hydroxymethylglutaryl-CoA Reductase Inhibitors - blood; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Male; Middle Aged; Neoplasm Proteins - genetics; Organic Anion Transporters - genetics; Pharmacokinetics and Disposition; Pharmacology; Pharmacology/Toxicology; Polymorphism; Polymorphism, Single Nucleotide - genetics; Rosuvastatin Calcium - adverse effects; Rosuvastatin Calcium - blood; Rosuvastatin Calcium - pharmacokinetics; Simvastatin - adverse effects; Simvastatin - analogs & derivatives; Simvastatin - blood; Simvastatin - pharmacokinetics; Solute Carrier Organic Anion Transporter Family Member 1b1; Statins; White people; Young Adult; Caucasian; Pharmacogenetics; Pharmacokinetics; Asian
• DOI: 10.1007/s00228-014-1801-z
• ISSN: 0031-6970; 1432-1041

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.