ABCG2 Polymorphism Is Associated With the Low‐Density Lipoprotein Cholesterol Response to Rosuvastatin

The ATP‐binding cassette G2 (ABCG2) c.421C>A (rs2231142) polymorphism influences the pharmacokinetics of rosuvastatin. We examined whether this polymorphism influences the low‐density lipoprotein cholesterol (LDL‐C)‐lowering efficacy of the drug. In 305 Chinese patients with hypercholesterolemia who were treated with rosuvastatin at a dosage of 10 mg daily, the c.421A variant was found to be significantly associated with greater reduction in LDL‐C level, in a gene‐dose‐dependent manner. As compared with subjects with the c.421CC genotype, those with the c.421AA genotype showed a 6.9% greater reduction in LDL‐C level, which would be equivalent to the effect obtained by doubling the dose of rosuvastatin.

[1]  G. Kéri,et al.  High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. , 2004, Molecular pharmacology.

[2]  M. Waye,et al.  Pharmacogenetics of HMG-CoA Reductase Inhibitors: Optimizing the Prevention of Coronary Heart Disease , 2009 .

[3]  A. Hofman,et al.  Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study , 2008, The Lancet.

[4]  K. Maeda,et al.  SLCO1B1 (OATP1B1, an Uptake Transporter) and ABCG2 (BCRP, an Efflux Transporter) Variant Alleles and Pharmacokinetics of Pitavastatin in Healthy Volunteers , 2007, Clinical pharmacology and therapeutics.

[5]  K. Sim,et al.  A randomised study comparing the efficacy and safety of rosuvastatin with atorvastatin for achieving lipid goals in clinical practice in Asian patients at high risk of cardiovascular disease (DISCOVERY-Asia study) , 2007, Current medical research and opinion.

[6]  R. Rosenson.  Rosuvastatin: a new inhibitor of HMG-CoA reductase for the treatment of dyslipidemia , 2003, Expert review of cardiovascular therapy.

[7]  R. Kim,et al.  Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. , 2006, Gastroenterology.

[8]  R. Collins,et al.  SLCO1B1 variants and statin-induced myopathy--a genomewide study. , 2008, The New England journal of medicine.

[9]  A. Nafziger,et al.  Evaluation of inhibitory drug interactions during drug development: Genetic polymorphisms must be considered , 2005, Clinical pharmacology and therapeutics.

[10]  H. Schuster.  Rosuvastatin – A Highly Effective New 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor: Review of Clinical Trial Data at 10–40 mg Doses in Dyslipidemic Patients , 2003, Cardiology.

[11]  S. Xenophontos,et al.  Genetic and environmental factors affecting the response to statin therapy in patients with molecularly defined familial hypercholesterolaemia , 2005, Pharmacogenetics and genomics.

[12]  S. Grundy.  The issue of statin safety: where do we stand? , 2005, Circulation.

[13]  E. Schaefer,et al.  Pharmacogenetics of HMG-CoA reductase inhibitors: exploring the potential for genotype-based individualization of coronary heart disease management. , 2004, Atherosclerosis.

[14]  R. Kim,et al.  Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants , 2007, Pharmacogenetics and genomics.

[15]  Junjeong Choi,et al.  Influence of OATP1B1 Genotype on the Pharmacokinetics of Rosuvastatin in Koreans , 2008, Clinical pharmacology and therapeutics.

[16]  E. Tai,et al.  Do Singapore patients require lower doses of statins? The SGH Lipid Clinic experience. , 2003, Singapore medical journal.

[17]  E. Tai,et al.  Do Singapore Patients Require Lower Doses of Statins? The SGH Lipid Clinic Experience , 2004 .

[18]  W. Roberts.  The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. , 1997, The American journal of cardiology.

[19]  S. Grimm,et al.  ATP-DEPENDENT TRANSPORT OF ROSUVASTATIN IN MEMBRANE VESICLES EXPRESSING BREAST CANCER RESISTANCE PROTEIN , 2006, Drug Metabolism and Disposition.

[20]  P. Neuvonen,et al.  ABCG2 Polymorphism Markedly Affects the Pharmacokinetics of Atorvastatin and Rosuvastatin , 2009, Clinical pharmacology and therapeutics.

[21]  B. Tomlinson,et al.  Mutations in the low-density lipoprotein receptor gene in Chinese familial hypercholesterolemia patients. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[22]  E. Schuetz,et al.  Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine. , 2003, Pharmacogenetics.

[23]  Ya-li Liu,et al.  Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. , 2006, Clinica chimica acta; international journal of clinical chemistry.

[24]  Eun-Young Kim,et al.  Identification and Functional Assessment of BCRP Polymorphisms in a Korean Population , 2007, Drug Metabolism And Disposition.

[25]  Yuichi Sugiyama,et al.  Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. , 2006, Pharmacology & therapeutics.

[26]  P. Neuvonen,et al.  Different Effects of SLCO1B1 Polymorphism on the Pharmacokinetics of Atorvastatin and Rosuvastatin , 2007, Clinical pharmacology and therapeutics.

[27]  Caroline A. Lee,et al.  Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment , 2005, Clinical pharmacology and therapeutics.

[28]  Y. Sugiyama,et al.  Functional Analysis of SNPs Variants of BCRP/ABCG2 , 2004, Pharmaceutical Research.

[29]  R. Tirona.  Ethnic differences in statin disposition , 2005, Clinical pharmacology and therapeutics.

[30]  R. Collins,et al.  Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths , 2007, The Lancet.