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).

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.

Triazole derivative

Fluconazole is indicated for the treatment of fungal infections. It is administered orally and intravenously. Plasma elimination half-life is approximately 30 hours.

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).

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.