Monograph
C10AA02 - Lovastatin |
Propably not porphyrinogenic |
PNP |
Rationale
Lovastatin is not listed as an inhibitor or inducer of CYP3A4 in humans.
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
Lovastatin is indicated for the treatment of hypercholesterolemia. It is given as a lactone prodrug.
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 constipation, diarrhoea, nausea and dyspepsia. Other common side effects are abdominal pain and myalgia. Less common side effects are fatigue and loss of appetite.
Metabolism and pharmacokinetics
Lovastatin is metabolized mainly by CYP3A4 (Corsini 1999, Masubuchi 2007) to the active betahydroxyacid. Lovastatin is not an inhibitor of CYP3A4 (Hisaka 2010, Isoherranen 2009, SPC).
In vitro studies have shown that lovastatin increased the expression of CYP2C9 which was mediated through CAR (Bertrand-Thiebault 2007). Other in vitro studies have shown that lovastatin activate PXR, and induce CYP3A and CYP2B6 (Dickins 2004, Kliewer 1999, Kocarek 2002), but it is not listed as an inducer of CYP enzymes in humans (Dickins 2004, Hisaka 2010, Pelkonen 2008).
References
| # | Citation details | PMID |
|---|---|---|
| * | Scientific articles | |
| 1. | Effect of HMGCoA reductase inhibitors on cytochrome P450 expression in endothelial cell line.
Bertrand-Thiebault C, Masson C, et al. J Cardiovasc Pharmacol. 2007 May;49(5):306-15. |
17513950 |
| 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. | The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways.
Kliewer SA, Lehmann JM, et al. Recent Prog Horm Res. 1999;54:345-67; discussion 367-8. |
10548883 |
| 7. | 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 |
| 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. | 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 |
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