Effects of polymorphisms in ABCG2, SLCO1B1, SLC10A1 and CYP2C9/19 on plasma concentrations of rosuvastatin and lipid response in Chinese patients.
OBJECTIVE
This study examined whether the ABCG2 421C>A polymorphism and variants in other genes potentially related to the pharmacokinetics of rosuvastatin influenced the plasma concentration of rosuvastatin in Chinese patients with hypercholesterolemia.


METHODS
Overnight fasting blood samples were collected from 291 patients who had received a rosuvastatin 10 mg night-time dose for at least 4 weeks. Plasma concentrations of rosuvastatin and N-desmethyl rosuvastatin were quantified using liquid chromatography tandem mass spectrometry.


RESULTS
In subjects with the ABCG2 421AA genotype (n = 39), the mean plasma concentrations of rosuvastatin and its metabolite were 63 and 41% greater than the values in those with the 421CA genotype (n = 108) and 120 and 99% greater than in those with the 421CC genotype (n = 129). The plasma concentrations of rosuvastatin were associated (r = -0.194; p = 0.001) with the percentage reduction in low-density lipoprotein cholesterol with rosuvastatin, but the association was not significant after adjusting for the ABCG2 421C>A polymorphism. The SLCO1B1 521T>C polymorphism was associated with increased plasma concentrations of rosuvastatin and impaired N-demethylation of rosuvastatin, but had no impact on its lipid-lowering effect. Polymorphisms in CYP2C9, CYP2C19 and SLC10A1 had minimal effects.


CONCLUSIONS
These findings suggest that the increased plasma concentrations of rosuvastatin in Chinese patients are associated with increased lipid-lowering effects and lower doses of rosuvastatin should be effective in subjects with the ABCG2 421C>A variant.
Department of Medicine & Therapeutics, The Chinese University of Kong Kong, Shatin, Hong Kong SAR, China.
Hon-Kit
HK
Lee
Miao
M
Hu
Sandra Sh
SSh
Lui
Chung-Shun
CS
Ho
Chun-Kwok
CK
Wong
Brian
B
Tomlinson
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005464:Fluorobenzenes / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D056726:Genetic Association Studies; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D027361:Organic Anion Transporters / Q000235:genetics*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D027981:Symporters / Q000235:genetics*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D008078:Cholesterol, LDL; D005464:Fluorobenzenes; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D011743:Pyrimidines; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; D027981:Symporters; C071908:sodium-bile acid cotransporter; D000068718:Rosuvastatin Calcium; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases