Molecular Diagnosis & Therapy

, Volume 17, Issue 4, pp 233–237 | Cite as

UGT1A1*28 is Associated with Decreased Systemic Exposure of Atorvastatin Lactone

  • Camilla Stormo
  • Martin P. Bogsrud
  • Monica Hermann
  • Anders Åsberg
  • Armin P. Piehler
  • Kjetil Retterstøl
  • Marianne K. Kringen
Short Communication

Abstract

Background

Atorvastatin is commonly used to reduce cholesterol. Atorvastatin acid is converted to its corresponding lactone form spontaneously or via glucuronidation mediated by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A3. Atorvastatin lactone is pharmacologically inactive, but is suspected to be muscle toxic and cause statin-induced myopathy (SIM). A several fold increase in systemic exposure of atorvastatin lactone has previously been observed in patients with SIM compared with healthy control subjects. In this study we aimed to investigate the association between polymorphisms in the UGT1A gene locus and plasma atorvastatin lactone levels.

Methods

DNA was extracted from whole blood obtained from a previous pharmacokinetic study of patients carefully diagnosed as having true SIM (n = 13) and healthy control subjects (n = 15). The UGT1A1*28(TA)7, UGT1A3*2, UGT1A3*3, and UGT1A3*6 polymorphisms were detected by pyrosequencing.

Results

Carriers of the low-expression allele UGT1A1*28(TA)7 tended to have lower levels of atorvastatin lactone (p < 0.05) than carriers with the normal-activity allele (TA)6.

Conclusion

The low-expression UGT1A1*28(TA)7 allele seems to be associated with decreased systemic exposure of the suspected muscle-toxic metabolite atorvastatin lactone.

Reference

  1. 1.
    Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–81.PubMedCrossRefGoogle Scholar
  2. 2.
    Chatzizisis YS, Koskinas KC, Misirli G, et al. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf. 2010;33(3):171–87.PubMedCrossRefGoogle Scholar
  3. 3.
    Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy—a genome wide study. N Engl J Med. 2008;359(8):789–99.PubMedCrossRefGoogle Scholar
  4. 4.
    Hermann M, Bogsrud MP, Molden E, et al. Exposure of atorvastatin is unchanged but lactone and acid metabolites are increased several-fold in patients with atorvastatin-induced myopathy. Clin Pharmacol Ther. 2006;79(6):532–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Jacobsen W, Kuhn B, Soldner A, et al. Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. Drug Metab Dispos. 2000;28(11):1369–78.PubMedGoogle Scholar
  6. 6.
    Chen C, Mireles RJ, Campbell SD, et al. Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos. 2005;33(4):537–46.PubMedCrossRefGoogle Scholar
  7. 7.
    Skottheim IB, Gedde-Dahl A, Hejazifar S, et al. Statin induced myotoxicity: the lactone forms are more potent than the acid forms in human skeletal muscle cells in vitro. Eur J Pharm Sci. 2008;33(4–5):317–25.PubMedCrossRefGoogle Scholar
  8. 8.
    Skottheim IB, Bogsrud MP, Hermann M, et al. Atorvastatin metabolite measurements as a diagnostic tool for statin-induced myopathy. Mol Diagn Ther. 2011;15(4):221–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Riedmaier S, Klein K, Hofmann U, et al. UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo. Clin Pharmacol Ther. 2010;87(1):65–73.PubMedCrossRefGoogle Scholar
  10. 10.
    Cho SK, Oh ES, Park K, et al. The UGT1A3*2 polymorphism affects atorvastatin lactonization and lipid-lowering effect in healthy volunteers. Pharmacogenet Genomics. 2012;22(8):598–605.PubMedCrossRefGoogle Scholar
  11. 11.
    Court MH. Michael H. Court’s (2005–2008) online calculator. Tufts University web site. 2 May 22011. http://www.tufts.edu/~mcourt01/Documents/Court%20lab%20-%20HW%20calculator.xls.. Accessed 26 Mar 2012.
  12. 12.
    Carter KW, McCaskie PA, Palmer LJ. JLIN: a java based linkage disequilibrium plotter. BMC Bioinforma. 2006;7:60.CrossRefGoogle Scholar
  13. 13.
    Prueksaritanont T, Subramanian R, Fang X, et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos. 2002;30(5):505–12.PubMedCrossRefGoogle Scholar
  14. 14.
    Iolascon A, Faienza MF, Centra M, et al. (TA)8 allele in the UGT1A1 gene promoter of a Caucasian with Gilbert’s syndrome. Haematologica. 1999;84(2):106–9.PubMedGoogle Scholar
  15. 15.
    Laaksonen R. On the mechanisms of statin-induced myopathy. Clin Pharmacol Ther. 2006;79(6):529–31.PubMedCrossRefGoogle Scholar
  16. 16.
    Voora D, Shah SH, Spasojevic I, et al. The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J Am Coll Cardiol. 2009;54(17):1609–16.PubMedCrossRefGoogle Scholar
  17. 17.
    Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A. 1998;95(14):8170–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Camilla Stormo
    • 1
  • Martin P. Bogsrud
    • 2
    • 3
  • Monica Hermann
    • 4
  • Anders Åsberg
    • 4
  • Armin P. Piehler
    • 5
  • Kjetil Retterstøl
    • 3
  • Marianne K. Kringen
    • 6
  1. 1.Department of Medical BiochemistryOslo University Hospital, University of OsloOsloNorway
  2. 2.Helse Møre and Romsdal Health Trust, Department of Internal Medicine Ålesund and University of Oslo Ålesund HospitalÅlesundNorway
  3. 3.Lipid ClinicOslo University HospitalOsloNorway
  4. 4.School of PharmacyUniversity of OsloOsloNorway
  5. 5.Fürst Medical LaboratoryOsloNorway
  6. 6.Department of PharmacologyOslo University HospitalOsloNorway

Personalised recommendations