KETOCONAZOLE

It is a widely used fungicide.

Toxicokinetics: The oral absorption of ketoconazole is increased in an acidic environment.

 Ketoconazole is extensively metabolized in the liver and is eliminated primarily in the bile, but it is also passed in the milk.

Mechanism of Action.:

 Ketoconazole inhibits fungal replication by interfering with erosterol synthesis, specifically sterol 14-alpha-demethylase. This enzyme contains a group that is similar to cytochrome P-450.

 It is thought that ketoconazole may also act directly on the fungal cell membrane.

 Ketoconazole can inhibit testosterone synthesis.

Ketoconazole is a teratogen, which must be considered before beginning therapy. The mechanism of hepatotoxicity is not well understood and does not appear to be immune mediated.

Clinical Signs:

 Clinical signs are most commonly associated with gastrointestinal distress: anorexia, weight loss, vomiting, and diarrhea.

Hepatotoxicosis has also been reported in cats.

Clinical Pathology: Animals with hepatotoxicosis may exhibit elevated bilirubin concentrations as well as increased hepatic enzymes.

Lesions:  Evidence of massive centrilobular necrosis and cholestasis may be found in the intoxicated animal.

 Treatment. If an animal exhibits signs of hepatotoxicosis, the drug should be discontinued. No specific antidote exists and the animal must be provided with symptomatic and supportive therapy.

If an acute oral ingestion has occurred, oral administration of, or gastric lavage with, sodium bicarbonate may be considered in addition to symptomatic and supportive therapy.

Prognosis. Mild hepatotoxicosis is generally reversible after termination of the drug