Pharmacogenetic determinants of variability in lipid-lowering response to pravastatin therapy

Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan.
Journal of Human Genetics (Impact Factor: 2.46). 02/2006; 51(9):822-6. DOI: 10.1007/s10038-006-0025-1
Source: PubMed


Pravastatin is mainly taken up from the circulation into the liver via organic anion-transporting polypeptide 1B1 (SLCO1B1 gene product). We examined the contribution of genetic variants in the SLCO1B1 gene and other candidate genes to the variability of pravastatin efficacy in 33 hypercholesterolemic patients. In the initial phase of pravastatin treatment (8 weeks), heterozygous carriers of the SLCO1B1*15 allele had poor low-density lipoprotein cholesterol (LDL-C) reduction relative to non-carriers (percent reduction: -14.1 vs -28.9%); however, the genotype-dependent difference in the cholesterol-lowering effect disappeared after 1 year of treatment. Cholesterol 7alpha-hydroxylase (CYP7A1) and apolipoprotein E (APOE) are known to contribute to lipid metabolism. Homozygous carriers of the CYP7A1 -204C allele or heterozygotes for both CYP7A1 -204C and APOE epsilon4 alleles showed significantly poorer LDL-C reduction compared to that in other genotypic groups after 1 year of treatment (-24.3 vs -33.1%). These results suggest that the SLCO1B1*15 allele is associated with a slow response to pravastatin therapy, and the combined genotyping of CYP7A1 and APOE genes is a useful index of the lipid-lowering effect of pravastatin.

21 Reads
  • Source
    • "polypharmacy may lead to competition for a common metabolic pathway, which may increase statin concentrations and its dose-related AEs [45] [78]. Due to pharmacogenomics differences such as those that affect statin hepatic uptake, clearance, and CYP pathways between individuals, the response to individual statins in terms of efficacy and tolerability may differ among patients [45] [79] [80] [81]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiovascular diseases (CVD) are common and very well-known diseases that affect a large number of people. One of the common leading causes of CVD is a high level of lipids which eventually leads to atherosclerosis and CVD. Various types of medications having different mechanisms of action were introduced to control CVD. Among the frequently used drugs is statins. Statins have a very intense effect on lowering lipids, yet they are associated with a variety of side effects. Moreover, statins have low bioavailability, similarly to other lipid lowering medications. Therefore, several attempts were made to enhance their bioavailability. This chapter discusses a number of drugs used to lower lipid levels in the blood, their adverse effects and methods to improve their bioavailability.
    Commonly Used Drugs - Uses, Side Effects, Bioavailability & Approaches to Improve it, 1 edited by Rafik Karaman, 01/2015: chapter 4: pages 131-172; Nova Science Publishers., ISBN: 978-1-63463-828-9
  • Source
    • "Although many studies have evaluated the influence of APOE polymorphism on statin response, some of these studies had controversial results. Whereas there is a strong line of evidence linking APOE ε2/ε3/ε4 genotypes with the efficacy of statin treatment [23-26], other studies did not reveal any association between APOE genotypes and response to treatments with various statins [27-29]. Commonly, evidence supports that APOE ε3 allele is associated with better response than ε4 allele in term of LDL cholesterol decrease and, in addition, individuals carrying the ε2 allele have greater reduction of LDL cholesterol than ε3 homozygotes [30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Apolipoprotein E (apoE) is a key component of the lipid metabolism. Polymorphisms at the apoE gene (APOE) have been associated with cardiovascular disease, lipid levels and lipid-lowering response to statins. We evaluated the effects on APOE expression of hypercholesterolemia, APOE ε2/ε3/ε4 genotypes and atorvastatin treatment in Brazilian individuals. The relationship of APOE genotypes and plasma lipids and atorvastatin response was also tested in this population. APOE ε2/ε3/ε4 and plasma lipids were evaluated in 181 normolipidemic (NL) and 181 hypercholesterolemic (HC) subjects. HC individuals with indication for lowering-cholesterol treatment (n = 141) were treated with atorvastatin (10 mg/day/4-weeks). APOE genotypes and APOE mRNA in peripheral blood mononuclear cells (PBMC) were analyzed by TaqMan real time PCR. HC had lower APOE expression than NL group (p < 0.05) and individuals with low APOE expression showed higher plasma total and LDL cholesterol and apoB, as well as higher apoAI (p < 0.05). Individuals carrying ε2 allele have reduced risk for hypercholesterolemia (OR: 0.27, 95% I.C.: 0.08-0.85, p < 0.05) and NL ε2 carriers had lower total and LDL cholesterol and apoB levels, and higher HDL cholesterol than non-carriers (p < 0.05). APOE genotypes did not affect APOE expression and atorvastatin response. Atorvastatin treatment do not modify APOE expression, however those individuals without LDL cholesterol goal achievement after atorvastatin treatment according to the IV Brazilian Guidelines for Dyslipidemia and Atherosclerosis Prevention had lower APOE expression than patients with desirable response after the treatment (p < 0.05). APOE expression in PBMC is modulated by hypercholesterolemia and the APOE mRNA level regulates the plasma lipid profile. Moreover the expression profile is not modulated neither by atorvastatin nor APOE genotypes. In our population, APOE ε2 allele confers protection against hypercholesterolemia and a less atherogenic lipid profile. Moreover, low APOE expression after treatment of patients with poor response suggests a possible role of APOE level in atorvastatin response.
    Lipids in Health and Disease 11/2011; 10(1):206. DOI:10.1186/1476-511X-10-206 · 2.22 Impact Factor
  • Source
    • "In addition, the alteration of pharmacokinetics due to polymorphisms in SLCO1B1 may not be sufficient to affect the pharmacodynamics of pitavastatin. Takane et al26 reported that the SLCO1B1*15 allele was associated with a slow response to pravastatin therapy, and the combined genotype of CYP7A1 and APOE was a more useful index to predict the lipid-lowering effect of pravastatin. This implies that polymorphisms in other genes may play an important role in inter-individual variable response to statins. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the SLCO1B1 388A>G and 521T>C polymorphisms in hyperlipidemia patients and evaluate the effect of the two polymorphisms on the lipid-lowering efficacy of pitavastatin. The functional polymorphisms of SLCO1B1 (388A>G and 521T>C) were genotyped in 140 Chinese patients with essential hyperlipidemia using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and one-step tetra-primers ARMS-PCR. Eighty-five patients were enrolled in the clinical trial and given 2 mg of pitavastatin daily for 8 weeks. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) serum levels were measured at baseline, after 4 weeks and after 8 weeks of treatment. The allele frequencies of SLCO1B1 388A>G and 521T>C in essential hyperlipidemia patients were 71.1% and 11.1%, respectively. The 4- and 8-week treatment with pitavastatin significantly reduced TC, TG, and LDL levels, but there was no statistical difference among patients with wild type, SLCO1B1 388A>G or SLCO1B1 521T>C in the lipid-lowering efficacy of pitavastatin. The present study found that the allele frequencies of SLCO1B1 388A>G and 521T>C in Chinese patients with essential hyperlipidemia are comparable to those in healthy Chinese population. SLCO1B1 388A>G and 521T>C do not affect the lipid-lowering efficacy of pitavastatin.
    Acta Pharmacologica Sinica 02/2010; 31(3):382-6. DOI:10.1038/aps.2009.203 · 2.91 Impact Factor
Show more


21 Reads
Available from