Pharmacodynamics and mechanism of action
Ketoconazole, similar to other azole antifungals, is a fungistatic agent that causes growth arrest in fungal cells by inhibiting cell wall synthesis, thereby preventing the growth and spread of the fungus in the body.
Ketoconazole interacts with the enzyme 14-α-sterol demethylase, which is required for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased cellular permeability of the fungus due to the decreased amount of ergosterol in the fungal cell membrane. This metabolic inhibition also leads to the accumulation of toxic metabolites in the cell. This inhibits the growth of the fungus and prevents dissemination and multiplication.
Ketoconazole can only be absorbed from an acidic gastric environment. At pH values above 3, it becomes increasingly insoluble in water and absorption is thus greatly reduced. At a pH below 3, dissolution is complete after about 30 minutes. The bioavailability is about 76%. Ketoconazole is bound to plasma albumin by about 84% and to blood cells by another 15%. Ketoconazole is metabolized primarily by the CYP3A4 and CYP2D6 enzymes, with CYP3A4 accounting for the majority. Only 2-4% of the ketoconazole dose is excreted unchanged in the urine. Over 95% is excreted via hepatic metabolism.
Ketoconazole is an inhibitor of cytochromes in the liver. These are significantly involved in the metabolism of many drugs. This results in a high risk of drug-drug interactions. This risk is particularly increased for drugs that are metabolized by the CYP3A4 enzyme. Likewise, the use of antacids can greatly reduce the absorption of ketoconazole, resulting in a lack of effect.
However, since the use of ketoconazole is now largely limited to topical preparations, the overall risk of side effects is very low.