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