Skip to main content

Advertisement

SpringerLink
Log in

Lack of association between SLCO1B1 polymorphism and the lipid-lowering effects of atorvastatin and simvastatin in Chinese individuals

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

There is significant inter-individual variability in the lipid-lowering effects of atorvastatin and simvastatin. Our goal was to investigate the impact of SLCO1B1 genetic polymorphism on the lipid-lowering effects of atorvastatin and simvastatin.

Methods

We recruited 363 unrelated hyperlipidemic patients with the CYP3A4*1/*1, CYP3A5*1/*1, and CYP3AP1*1/*1 genotypes: 189 of these were treated with atorvastatin and 174 were treated with simvastatin as a single-agent therapy (20 mg day−1 orally) for 4 weeks. The genotyping of SLCO1B1 c.521T > C (p.V174A, OATP-C*5) was performed with allele-specific polymerase chain reaction (AS-PCR), and PCR restriction fragment length polymorphism (RFLP) was performed to detect the carriers of SLCO1B1 c.388A > G (p.N130D, OATP-C*1b). Serum triglyceride (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were determined before and after treatment.

Results

The frequencies of the SLCO1B1 521T > C and 388A > G variant alleles in Chinese hyperlipidemic patients were found to be 16.2% and 72.1% respectively. After treatment with 20 mg simvastatin or atorvastatin daily for 4 weeks, TC, TG, and LDL-C concentrations were lower than at baseline, on average, by 18.1 ± 3.7%, 25.8 ± 9.7%, 27.7 ± 5.4% in the simvastatin-treated group, and 17.5 ± 3.7%, 22.6 ± 8.6%, 27.5 ± 5.5% in the atorvastatin-treated group respectively, and the mean relative reduction in serum HDL cholesterol did not reach statistical significance (−1.0 ± 10.9%, 0.5 ± 9.3%). However, no significant differences were observed in the lipid-lowering effects of atorvastatin and simvastatin between subjects with different SLCO1B1 genotypes.

Conclusion

The SLCO1B1 521T > C and 388A > G variants were found to be relatively common in Chinese patients with essential hyperlipidemia. These frequencies were found to be similar to those observed in healthy Chinese and Japanese individuals, but significantly different from Caucasians and blacks. SLCO1B1 521T > C and 388A > G polymorphisms may not be associated with the lipid-lowering effects of atorvastatin and simvastatin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Vaughan CJ, Gotto AM, Basson CT (2000) The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol 35(1):1–10

    Article  PubMed  CAS  Google Scholar 

  2. Romaine SP, Bailey KM, Hall AS, Balmforth AJ (2010) The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy. Pharmacogenomics J 10(1):1–11

    Article  PubMed  CAS  Google Scholar 

  3. König J, Cui Y, Nies AT, Keppler D (2000) A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol 278(1):G156–G164

    PubMed  Google Scholar 

  4. Hagenbuch B, Meier PJ (2003) The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 1609(1):1–18

    Article  PubMed  CAS  Google Scholar 

  5. Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang WP, Kirchgessner TG (1999) A novel human hepatic organic anion transporting polypeptide (OATP2), identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem 274(52):37161–37168

    Article  PubMed  CAS  Google Scholar 

  6. Lau YY, Okochi H, Huang Y, Benet LZ (2006) Multiple transporters affect the disposition of atorvastatin and its two active hydroxy metabolites: application of in vitro and ex situ systems. J Pharmacol Exp Ther 316(2):762–771

    Article  PubMed  CAS  Google Scholar 

  7. Kameyama Y, Yamashita K, Kobayashi K, Hosokawa M, Chiba K (2005) Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15 + C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharmacogenet Genomics 15(7):513–522

    Article  PubMed  CAS  Google Scholar 

  8. Chen C, Mireles RJ, Campbell SD, Lin J, Mills JB, Xu JJ, Smolarek TA (2005) Differential interaction of 3-hydroxy-3-methylglutaryl-COA-reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos 33(4):537–546

    Article  PubMed  CAS  Google Scholar 

  9. Tirona RG, Leake BF, Wolkoff AW, Kim RB (2003) Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. J Pharmacol Exp Ther 304(1):223–228

    Article  PubMed  CAS  Google Scholar 

  10. Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M (2007) Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 82(6):726–733

    Article  PubMed  CAS  Google Scholar 

  11. Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M (2006) SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 16(12):873–879

    Article  PubMed  CAS  Google Scholar 

  12. Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I (2005) Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos 33(3):434–439

    Article  PubMed  CAS  Google Scholar 

  13. Deng JW, Song IS, Shin HJ, Yeo CW, Cho DY, Shon JH, Shin JG (2008) The effect of SLCO1B1*15 on the disposition of pravastatin and pitavastatin is substrate dependent: the contribution of transporting activity changes by SLCO1B1*15. Pharmacogenet Genomics 18(5):424–433

    Article  PubMed  CAS  Google Scholar 

  14. Tachibana-Iimori R, Tabara Y, Kusuhara H, Kohara K, Kawamoto R, Nakura J, Tokunaga K, Kondo I, Sugiyama Y, Miki T (2004) Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering response to HMG-CoA reductase inhibitors. Drug Metab Pharmacokinet 19(5):375–380

    Article  PubMed  CAS  Google Scholar 

  15. Gao Y, Zhang LR, Fu Q (2008) CYP3A4*1G polymorphism is associated with lipid-lowering efficacy of atorvastatin but not of simvastatin. Eur J Clin Pharmacol 64(9):877–882

    Article  PubMed  CAS  Google Scholar 

  16. Li YP, Zhang LR, Jia M, Hu XJ (2011) CYP3AP1*3 allele is associated with lipid-lowering efficacy of simvastatin and atorvastatin in Chinese women. J Clin Pharmacol 51(2):181–188

    Article  PubMed  CAS  Google Scholar 

  17. Nozawa T, Nakajima M, Tamai I, Noda K, Nezu J, Sai Y, Tsuji A, Yokoi T (2002) Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis. J Pharmacol Exp Ther 302(2):804–813

    Article  PubMed  CAS  Google Scholar 

  18. Tirona RG, Leake BF, Merino G, Kim RB (2001) Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African–Americans. J Biol Chem 276(38):35669–35675

    Article  PubMed  CAS  Google Scholar 

  19. Mwinyi J, Köpke K, Schaefer M, Roots I, Gerloff T (2008) Comparison of SLCO1B1 sequence variability among German, Turkish, and African populations. Eur J Clin Pharmacol 64(3):257–266

    Article  PubMed  CAS  Google Scholar 

  20. Pasanen MK, Backman JT, Neuvonen PJ, Niemi M (2006) Frequencies of single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide 1B1 SLCO1B1 gene in a Finnish population. Eur J Clin Pharmacol 62(6):409–415

    Article  PubMed  CAS  Google Scholar 

  21. Thompson JF, Man M, Johnson KJ, Wood LS, Lira ME, Lloyd DB, Banerjee P, Milos PM, Myrand SP, Paulauskis J, Milad MA, Sasiela WJ (2005) An association study of 43 SNPs in 16 candidate genes with atorvastatin response. Pharmacogenomics J 5(6):352–358

    Article  PubMed  CAS  Google Scholar 

  22. Illingworth DR, Erkelens DW, Keller U, Thompson GR, Tikkanen MJ (1994) Defined daily doses in relation to hypolipidaemic efficacy of lovastatin, pravastatin, and simvastatin. Lancet 343(8912):1554–1555

    Article  PubMed  CAS  Google Scholar 

  23. Marshall S, Meredith PA, Elliott HL (1994) Efficacy of low density-lipoprotein lowering with statins [letter]. Lancet 344(8923):684

    Article  PubMed  CAS  Google Scholar 

  24. Nawrocki JW, Weiss SR, Davidson MH, Sprecher DL, Schwartz SL, Lupien PJ, Jones PH, Haber HE, Black DM (1995) Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler Thromb Vasc Biol 15(5):678–682

    Article  PubMed  CAS  Google Scholar 

  25. Kerb R (2006) Implications of genetic polymorphisms in drug transporters for pharmacotherapy. Cancer Lett 234(1):4–33

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This project was supported by the National Natural Science Foundation of the People’s Republic of China (30850003) and the Science Foundation for Distinguished Young Scholars of Henan Province (No.074100510020).

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China

    Qiang Fu, Yan-Peng Li, Yuan Gao, Song-Hua Yang, Min Jia & Li-Rong Zhang

  2. The Third Affiliated Hospital, Zhengzhou University, Zhengzhou, China

    Qiang Fu

  3. The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China

    Yan-Peng Li, Song-Hua Yang & Pei-Qi Lu

Authors
  1. Qiang Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan-Peng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuan Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Song-Hua Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pei-Qi Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Min Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Li-Rong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Min Jia or Li-Rong Zhang.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 104 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fu, Q., Li, YP., Gao, Y. et al. Lack of association between SLCO1B1 polymorphism and the lipid-lowering effects of atorvastatin and simvastatin in Chinese individuals. Eur J Clin Pharmacol 69, 1269–1274 (2013). https://doi.org/10.1007/s00228-012-1453-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-012-1453-9

Keywords

Search

Navigation