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

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 s...

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Published in:European journal of clinical pharmacology 2015-03, Vol.71 (3), p.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: Article
Language:English
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
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Summary: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.
ISSN:0031-6970
1432-1041
DOI:10.1007/s00228-014-1801-z