Acute Porphyria Drugs

Acute Porphyria Drug Database

C10AA05 - Atorvastatin
Propably not porphyrinogenic
PNP
Rationale
Atorvastatin is a substrate of CYP3A4 and inhibits CYP3A4, but it is not listed as a mechanism-based inhibitor. Clinical data also indicates that it does not induce CYP3A4. Risk for gastrointestinal adverse events in the form of nausea and diarrhoea motivates vigilance against insufficient intake of food, especially of carbohydrate.
Chemical description
HMG-CoA reductase inhibitor
Therapeutic characteristics
Atorvastatin 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 obstipation, diarrhoea, nausea. Other less common side effects are vomiting and abdominal pain.
Metabolism and pharmakokinetics
Atorvastatin is metabolized by CYP3A4 (Corsini 1999, Masubuchi 2007, SPC). The elimination half-life is 14 hours. In vitro studies have shown that atorvastatin activate PXR, and induce CYP3A and CYP2B6 (Dickins 2004, Hoffart 2012, Kocarek 2002), but it is not listed as an inducer of CYP enzymes in humans (Hisaka 2010, Pelkonen 2008) Atorvastatin had no effect on the pharmacokinetics of midazolam, a CYP3A4 substrate, when co-administered. This may indicate that atorvastatin does not inhibit or induce CYP3A4 (Kokudai 2009). On the other hand, when atorvastatin was co-administered with norethindrone and ethinylestradiol the AUC increased by 28 % and 19 % respectively (SPC). These data indicates that atorvastatin may inhibit CYP3A4, but it is not listed as a mechanism-based inhibitor (Isoherranen 2009). Co-administration of atorvastatin and sirolimus, a major substrate and a minor inhibitor of CYP3A4, resulted in an increased mean trough concentration of sirolimus by 25%. After 5 months the trough concentration had increased by 61%. This may indicate that atorvastatin inhibited CYP3A4, but it is also important to take into consideration that sirolimus probably contributed as well (Barshes 2003). These data also indicates that atorvastatin does not induce CYP3A4.
Personal communication
Thunell, patient report (n=1): tolerated. Andersson, patient report (n=2): tolerated.
IPNet drug reports
Uneventful use reported in 24 patients with acute porphyria.

References

  1. Scientific articles
  2. Barshes NR, Goodpastor SE, Goss JA. Sirolimus-atorvastatin drug interaction in the pancreatic islet transplant recipient. Transplantation. 2003 Dec 15;76(11):1649-50. PMID 14702546. #1342
  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. Hoffart E, Ghebreghiorghis L, et al. Effects of atorvastatin metabolites on induction of drug-metabolizing enzymes and membrane transporters through human pregnane X receptor. Br J Pharmacol. 2012 Mar;165(5):1595-608. PMID 21913896. #4425
  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. 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
  10. 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
  11. 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
  12. Summary of Product Characteristics
  13. Norwegian medicines agency. Summary of Product Characteristics (SPC). Atorvastatin. #1344
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