Ketoconalzole-An Aquatic Pollutant: Sources, Impact, And Regulatory Aspects

Abstract

Ketoconazole is a common imidazole antifungal medication used in both human and veterinary medicine to remedy for a range of fungal infections.

It exhibits fungicidal and fungistatic activities against fungi such as dermatophytes, yeasts, and eumycetes. Its primary mechanism involves inhibiting cytochrome P450 enzymes, crucial for ergosterol synthesis, thereby disrupting fungal cell membranes and leading to fungal death or growth inhibition. It has been used commonly in pharmaceutical and healthcare products that can leave residual amounts of certain compounds, which may result in adverse ecological health issues. Research on ketoconazole (KTZ) underscores its environmental impact and regulatory concerns, particularly regarding toxicity in aquatic ecosystems. Key findings include:

Toxicity: KTZ, along with other azole fungicides, shows significant toxicity to aquatic plants like Lemna minor and heightened sensitivity in Daphnia similis. Synergistic Effects: KTZ can amplify toxicity when combined with substances like erythromycin, leading to greater bioaccumulation in fish and adverse biochemical effects. Endocrine Disruption: KTZ disrupts reproductive and metabolic functions in aquatic organisms, with potential negative outcomes from co-exposure to estrogens. Environmental Persistence: KTZ has a long half-life and high water solubility, posing risks of groundwater contamination and effects on non-target species. Human Health Risks: Its impact on aquatic ecosystems, including potential links to increased fungal resistance, raises concerns for human health via environmental exposure. These findings highlight the need for further research on KTZ and azole compounds to assess their ecological effects.

 KTZ faces regulatory challenges due to safety concerns, primarily its ability to elevate plasma levels of other drugs, leading to adverse effects like QT prolongation. The FDA has restricted its use, recommending against it as a first-line treatment for fungal infections but allowing it for life-threatening systemic mycoses when alternatives are unavailable. In contrast, the European Medicines Agency (EMA) has approved KTZ in the EU, citing its benefits for treating Cushing's syndrome as outweighing risks, while the CHMP believes liver-related risks can be managed. In Australia, the TGA has deregistered KTZ's oral form due to liver injury concerns, though topical formulations remain available. Overall, KTZ's therapeutic potential is recognized, but its regulatory status reflects ongoing safety concerns.

Despite this, it remains approved for specific conditions with safety managed through risk minimization measures.