Acute Porphyria Drugs

Acute Porphyria Drug Database

C10AA04 - Fluvastatin
Propably not porphyrinogenic
PNP
Rationale
Fluvastatin is a weak inhibitor of CYP2C9, but is not listed as a mechanism-based inhibitor. It is not listed as an inducer of CYP enzymes. Risk for gastrointestinal adverse events in the form of nausea motivates vigilance against insufficient intake of food, especially of carbohydrate.
Chemical description
HMG-CoA reductase inhibitor
Therapeutic characteristics
Fluvastatin is indicated for the treatment of hypercholesterolemia and cardiovascular prevention. Common side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack are nausea, dyspepsia and abdominal pain. Another common side effect is insomnia.
Metabolism and pharmakokinetics
Fluvastatin is mainly metabolized by CYP2C9 (Corsini 1999, Masubuchi 2007), but is also metabolized by CYP3A4, CYP2C8 and CYP2D6 (Norsk legemiddelhåndbok, Scripture 2001). The elimination half-life is 2-3 hours. In vitro studies have shown that fluvastatin increased the expression of CYP2C9 which was mediated through CAR (Bertrand-Thiebault 2007). Other in vitro studies have shown that fluvastatin induce CYP3A and CYP2B effectively (Dickins 2004, Kocarek 2002), but it is not listed as an inducer of CYP enzymes in humans (Hisaka 2010, Pelkonen 2008). Losartan is primarily converted to the metabolite E-3174 by CYP2C9. Co-administration of losartan with fluvastatin did not affect the metabolism of losartan, which may indicate that fluvastatin do not inhibit or induce CYP2C9 (Meadowcroft 1999, Scripture 2001). Fluvastatin have however, increased the AUC of tolbutamide by 23 % (Appel 1995, Meadowcroft 1999) and the AUC of glibenclamide by 19 % (Appel 1995). They are CYP2C9-substrates, which indicates that fluvastatin is an inhibitor of CYP2C9. Fluvastatin is listed as a weak inhibitor of CYP2C9 in vivo (Isoherranen 2009, Scripture 2001), but is on the other hand not listed as a mechanism-based inhibitor (Pelkonen 2008). An in vitro study has showed that it is a non-competitive inhibitor of CYP3A4 (McDonnell 2005).

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. Bertrand-Thiebault C, Masson C, et al. Effect of HMGCoA reductase inhibitors on cytochrome P450 expression in endothelial cell line. J Cardiovasc Pharmacol. 2007 May;49(5):306-15. PMID 17513950. #4422
  4. 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
  5. Dickins M. Induction of cytochromes P450. Curr Top Med Chem. 2004;4(16):1745-66. PMID 15579106. #1323
  6. 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
  7. 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
  8. 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
  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. Mc Donnell CG, Shorten G, Van Pelt FN. Effect of atorvastatin and fluvastatin on the metabolism of midazolam by cytochrome P450 in vitro. Anaesthesia. 2005 Aug;60(8):747-53. #1337
  11. Meadowcroft AM, Williamson KM, et al. The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers. J Clin Pharmacol. 1999 Apr;39(4):418-24. PMID 10197301. #4424
  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. Scripture CD and Pieper JA. Clinical pharmacokinetics of fluvastatin. Clin Pharmacokinet. 2001;40(4):263-81. PMID 11368292. #1341
  14. Drug reference publications
  15. Norsk legemiddelhåndbok. Fluvastatin. #1340
  16. Drug interaction databases
  17. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed [DATE]. #1336
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