Acute Porphyria Drugs

Acute Porphyria Drug Database

C10AA01 - Simvastatin
Propably not porphyrinogenic
PNP
Important Information
Important info Lorem Ipsum
Rationale
Simvastatin is a substrate of CYP enzymes. Clinical data indicates that it does not inhibit or induce CYP3A4. Data also indicates that it is a weak inhibitor of CYP2C9, but it is not listed as a mechanism-based inhibitor.
Chemical description
HMG-CoA reductase inhibitor
Therapeutic characteristics
Simvastatin is indicated for the treatment of hypercholesterolemia and cardiovascular prevention. It is given as a lactone prodrug. Less common side effects are constipation, abdominal pain, dyspepsia, diarrhoea, nausea and vomiting.
Metabolism and pharmakokinetics
Simvastatin is metabolized primarily by CYP3A4 (Corsini 1999, Flockhart 2007, Masubuchi 2007), CYP3A5 and CYP2C8 (Neuvonen 2008, Pelkonen 2008) to the active simvastatin hydroxyacid and other inactive metabolites. It is also metabolized to a lesser extent by CYP2C9 and CYP2D6 (Sconce 2006). In vitro studies have shown that simvastatin activate PXR, and induce CYP3A (Yamasaki 2009, Dickins 2004, Kocarek 2002) and CYP2B6 (Dickins 2004, Kocarek 2002), but it is not listed as an inducer of CYP enzymes in humans (Dickins 2004, Hisaka 2010, Pelkonen 2008). Other in vitro studies have shown that it inhibits the activity of CYP3A (Prueksaritanont 1997, Rendic 2002, Teramura 1997), but it does not inhibit CYP2C8, CYP2C9, CYP2C19 and CYP2D6 in human liver microsomes (Prueksaritanont 1997). Simvastatin had no effect on the pharmacokinetics of midazolam, a CYP3A4 substrate, when co-administered. This may indicate that simvastatin does not inhibit or induce CYP3A4 (Kokudai 2009). Another in vivo study concluded that simvastatin had no apparent effects on the pharmacokinetics of imatinib, a CYP3A4 substrate, (O’Brien 2003) which also indicates that simvastatin does not inhibit or induce CYP3A4. A clinical study showed that simvastatin increased the AUC of glibenclamide, a CYP2C9 substrate, by 28 % (Appel 1995), which indicates that it is an inhibitor of CYP2C9. Simvastatin is however, not listed as a mechanism-based inhibitor of CYP enzymes (Isoherranen 2009).
Personal communication
Andersson, patient report (n=5): tolerated. Thunell, patient report (n=2): tolerated.
Published experience
European Porphyria Network: not listed. Porphyria South Africa: use only with extreme caution and if no alternative.
IPNet drug reports
Uneventful use reported in 14 patients with acute porphyria.

References

  1. Scientific articles
  2. Appel S, Rüfenacht T, et al. Lack of interaction between fluvastatin and oral hypoglycemic agents in healthy subjects and in patients with non-insulin-dependent diabetes mellitus. Am J Cardiol. 1995 Jul 13;76(2):29A-32A. PMID 7604792. #4416
  3. Corsini A, Bellosta S, et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther. 1999 Dec;84(3):413-28. #1322
  4. Dickins M. Induction of cytochromes P450. Curr Top Med Chem. 2004;4(16):1745-66. PMID 15579106. #1323
  5. Hisaka A, Ohno Y, et al. Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information. Pharmacol Ther. 2010 Feb;125(2):230-48. #1138
  6. Isoherranen N, Hachad H, et al. Qualitative analysis of the role of metabolites in inhibitory drug-drug interactions: literature evaluation based on the metabolism and transport drug interaction database. Chem Res Toxicol. 2009 Feb;22(2):294-8. #1005
  7. Kocarek TA, Dahn MSm, et al. Regulation of CYP2B6 and CYP3A expression by hydroxymethylglutaryl coenzyme A inhibitors in primary cultured human hepatocytes. Drug Metab Dispos. 2002 Dec;30(12):1400-5. PMID 12433810. #4417
  8. Kokudai M, Inui N, et al. Effects of statins on the pharmacokinetics of midazolam in healthy volunteers. J Clin Pharmacol. 2009 May;49(5):568-73. #1325
  9. Masubuchi Y, Horie T. Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs. Crit Rev Toxicol. 2007 Jun;37(5):389-412. PMID 17612953. #1326
  10. Neuvonen PJ, Backman JT, Niemi M. Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin. Clin Pharmacokinet. 2008;47(7):463-74. PMID 18563955. #1327
  11. OBrien SG, Meinhardt P, et al. Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer. 2003 Nov 17;89(10):1855-9. PMID 14612892. #4418
  12. Pelkonen O, Turpeinen M, et al. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol. 2008 Oct;82(10):667-715. PMID 18618097. #4347
  13. Prueksaritanont T, Gorham LM, et al. In vitro metabolism of simvastatin in humans [SBT]identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos. 1997 Oct;25(10):1191-9. PMID 9321523. #4419
  14. Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. PMID 11996015. #1039
  15. Sconce EA, Khan TI, et al. The impact of simvastatin on warfarin disposition and dose requirements. J Thromb Haemost. 2006 Jun;4(6):1422-4. PMID 16706996. #4420
  16. Teramura T, Fukunaga Y, et al. Examination of metabolic pathways and identification of human liver cytochrome P450 isozymes responsible for the metabolism of barnidipine, a calcium channel blocker. Xenobiotica. 1997 Sep;27(9):885-900. #1332
  17. Yamasaki D, Nakamura T, et al. Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells. Eur J Pharm Sci. 2009 May 12;37(2):126-32. PMID 19429419. #4421
  18. Drug interaction databases
  19. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). #1213
  20. Summary of Product Characteristics
  21. Norwegian medicines agency. Summary of Product Characteristics (SPC). simvastatin. #1328
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