Acute Porphyria Drugs

Acute Porphyria Drug Database

J02AC01 - Fluconazole
Probably porphyrinogenic
PRP
Side effects
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 abdominal pain, vomiting, diarrhoea and nausea. Other common side effects are headache and increased alanine aminotransferase and aspartate aminotransferase. Fluconazole should be administered with caution to patients with liver dysfunction. It has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. Azoles are inhibitors of CYP51 (lanosterol 14-α-demethylase) (Lepesheva 2007). CYP51 are involved in sterol synthesis and plays an essential role in formation of the cell membrane in fungi. Azoles bind to the heme group and form a covalent bond with the iron atom (Balding 2008).
Rationale
Fluconazole is an inhibitor of CYP3A4, CYP2C9 and CYP2C19. It interacts with the heme moiety of the CYP enzymes. The inhibition is thought to be reversible and is not found to be mechanism-based. There is one drug report of porphyrinogenicity and fluconazole might probably be porphyrinogenic.
Chemical description
Triazole derivative
Therapeutic characteristics
Fluconazole is indicated for the treatment of fungal infections. It is administered orally and intravenously. Plasma elimination half-life is approximately 30 hours.
Metabolism and pharmakokinetics
Fluconazole is metabolized only to a minor extent. The major route of excretion is renal and 80 % of an orally administered drug is excreted as unchanged drug (Nivoix 2008 and SPC). Plasma protein binding of fluconazole is low (SPC). Fluconazole is an inhibitor of CYP2C9, CYP2C19 and CYP3A4 (Pelkonen 2008 and SPC). It is listed as a moderate inhibitor of CYP2C9 and CYP3A4, and a strong inhibitor of CYP2C19 in vivo (FDA). In vitro data indicates that it is not a mechanism-based inhibitor of these enzymes (Niwa 2005) and it is not listed as a mechanism-based inhibitor in vivo (Isoherranen 2009 and Pelkonen 2008). Fluconazole exerts mixed-type (Nivoix 2008 and Pelkonen 2008) or non-competitive inhibition of CYP by interacting directly with the heme moiety of CYP2C9, CYP3A4 and CYP2C19 (Nivoix 2008). IC50 and IC50-shift experiments indicate that fluconazole is a reversible inhibitor of CYP3A4 and CYP2C9 (Berry 2008). Co-administration of fluconazole with midazolam reduced the mean clearance and increased the mean AUC values of oral midazolam by 50 % and 3.6-fold, respectively (Olkkola 1996). This confirms that fluconazole is an inhibitor of CYP3A4. The azole ketoconazole is a certain PXR antagonist in vitro (Duret 2006, Huang 2007 and Lim 2009), but there is conflicting information regarding fluconazole’s effect on PXR. Fluconazole has been reported not to antagonize PXR (Duret 2006 and Svecova 2008), whereas Wang et al. (2007) report that it is an antagonist in the presence of an PXR agonist, similar to ketoconazole. Both fluconazole and ketoconazole have also been reported to be weak agonists in the absence of a PXR ligand (Wang 2007).
IPNet drug reports
Uneventful use reported in 2 patients with acute porphyria. One report of an attack requiring hospitalisation in female AIP patient following the use of fluconazole, but the patient was also exposed to other factors that could have contributed to the attack.

References

  1. Scientific articles
  2. Balding PR, Porro CS, et al. How do azoles inhibit cytochrome P450 enzymes? A density functional study. J Phys Chem A. 2008 Dec 18;112(50):12911-8. PMID 18563875. #4509
  3. Berry LM, Zhao Z. An examination of IC50 and IC50-shift experiments in assessing time-dependent inhibition of CYP3A4, CYP2D6 and CYP2C9 in human liver microsomes. Drug Metab Lett. 2008 Jan;2(1):51-9. PMID 19356071. #1684
  4. Duret C, Daujat-Chavanieu M, et al. Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor. Mol Pharmacol. 2006 Jul;70(1):329-39. PMID 16608920. #4504
  5. Huang H, Wang H, et al. Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene. 2007 Jan 11;26(2):258-68. #1674
  6. Lepesheva GI, Waterman MR. Sterol 14alpha-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms. Biochim Biophys Acta. 2007 Mar;1770(3):467-77. PMID 16963187. #1685
  7. Lim YP, Kuo SC, et al. Inhibition of CYP3A4 expression by ketoconazole is mediated by the disruption of pregnane X receptor, steroid receptor coactivator-1, and hepatocyte nuclear factor 4alpha interaction. Pharmacogenet Genomics. 2009 Jan;19(1):11-24. PMID 19077665. #4510
  8. Nivoix Y, Levêque D, et al. The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clin Pharmacokinet. 2008;47(12):779-92. PMID 19026034. #4511
  9. Niwa T, Shiraga T, Takagi A. Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull. 2005 Sep;28(9):1805-8. PMID 16141567. #1688
  10. Olkkola KT, Ahonen J, Neuvonen PJ. The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg. 1996 Mar;82(3):511-6. PMID 8623953. #1690
  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. Svecova L, Vrzal R, et al. Azole antimycotics differentially affect rifampicin-induced pregnane X receptor-mediated CYP3A4 gene expression. Drug Metab Dispos. 2008 Feb;36(2):339-48. PMID 17998298. #4512
  13. Wang H, Huang H, et al. Activated pregnenolone X-receptor is a target for ketoconazole and its analogs. Clin Cancer Res. 2007 Apr 15;13(8):2488-95. PMID 17438109. #4508
  14. Government bodies
  15. #1302
  16. Drug interaction databases
  17. U.S.FoodandDrugAdministration (FDA). (27.10.2014)."Drug Developement and Drug Interactions: Table of Substrates, Inhibitors and Inducers." Retrieved 26.11.2015, from #1692
  18. Summary of Product Characteristics
  19. Norwegian medicines agency. Summary of Product characteristics (SPC). Flukonazol. #1689
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