Fluconazole Does Not Directly Cause Metabolic Acidosis
Fluconazole itself is not a recognized cause of metabolic acidosis based on extensive clinical experience and guideline documentation. The drug has been widely used for decades with well-characterized adverse effects that do not include metabolic acidosis as a direct toxicity.
Known Adverse Effects of Fluconazole
The documented adverse effects of fluconazole are well-established and do not include metabolic acidosis:
- Gastrointestinal effects: Nausea and vomiting are the most common adverse effects 1
- Hepatotoxicity: Asymptomatic transaminase elevations occur in 1-13% of patients, with rare cases of hepatitis 1
- Dermatologic reactions: Skin rash, pruritus, and alopecia; rare Stevens-Johnson syndrome 1
- Cardiac effects: QTc prolongation when combined with other QT-prolonging drugs 1
- Hematologic: Rare thrombocytopenia and leukopenia (more common with itraconazole than fluconazole) 1
Important Caveat: Drug Interactions
While fluconazole does not directly cause metabolic acidosis, it can indirectly contribute through drug-drug interactions:
- Fluconazole inhibits cytochrome P450 enzymes (particularly CYP2C9, CYP2C19, and to a lesser extent CYP3A4), which can increase plasma concentrations of co-administered drugs 1
- In one case report, fluconazole inhibited the metabolism of avatrombopag (a thrombopoietin receptor agonist), contributing to dose-dependent lactic acidosis—but the acidosis was caused by avatrombopag accumulation, not fluconazole itself 2
Renal Considerations
Fluconazole's renal profile does not predispose to metabolic acidosis:
- Primarily renally eliminated with minimal metabolism 3, 4
- Dose adjustment required when creatinine clearance is <50 mL/min 1
- Does not cause renal tubular acidosis or other renal mechanisms that would produce metabolic acidosis 5
- Among antifungals, amphotericin B has the highest nephrotoxicity potential, not fluconazole 5
Clinical Monitoring
If metabolic acidosis develops in a patient taking fluconazole:
- Investigate other causes: Sepsis, tissue hypoperfusion, renal failure, diabetic ketoacidosis, toxic ingestions 6
- Review all medications: Look for drugs that can cause lactic acidosis (metformin, antiretrovirals) or other forms of metabolic acidosis 6
- Consider drug interactions: Fluconazole may be elevating levels of another medication that causes acidosis 2
- Monitor liver function: Baseline and periodic monitoring (at 2 weeks, 4 weeks, then every 3 months) is recommended, particularly with prolonged therapy 7