Ketoconazole

Ketoconazole
ATC Code D01AC08, G01AF11, H02CA03, J02AB02
Formula C26H28Cl2N4O4
Molar Mass (g·mol−1) 531,43
Physical State solid
Melting Point (°C) 146
PKS Value 3.96
CAS Number 65277-42-1
PUB Number 456201
Drugbank ID DB01026
Solubility practically insoluble in water

Basics

Ketoconazole is an imidazole antifungal agent used to prevent and treat a range of fungal infections. It is characterized by a particularly broad spectrum of activity.

Ketoconazole was first approved by the U.S. Food and Drug Administration (FDA) in 1981 in an oral dosage form for systemic use. At that time, it was considered a significant improvement over previous antifungal agents due to its broad spectrum and good absorption. Because of frequent gastrointestinal side effects and the risk of dose-dependent hepatitis, the agent was relatively quickly replaced by substances from the triazole group, such as fluconazole, itraconazole, voriconazole, and posaconazole. Ketoconazole continues to be used in topical formulations.

Pharmacology

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.

Pharmacokinetics

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.

Drug Interactions

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.

Toxicity

Side effects

  • Nausea
  • Diarrhea
  • stomach pain
  • swelling of the chest
  • headache
  • Dizziness
  • abnormal liver enzyme levels

Contraindications and precautions

Ketoconazole should not be used if there is allergy to the substance or severe liver disease.

Markus Falkenstätter

Markus Falkenstätter
Author

Markus Falkenstätter ist Autor zu pharmazeutischen Themen in der Medizin-Redaktion von Medikamio. Er befindet sich im letzten Semester seines Pharmaziestudiums an der Universität Wien und liebt das wissenschaftliche Arbeiten im Bereich der Naturwissenschaften.

Mag. pharm Stefanie Lehenauer

Mag. pharm Stefanie Lehenauer
Lector

Stefanie Lehenauer ist seit 2020 freie Autorin bei Medikamio und studierte Pharmazie an der Universität Wien. Sie arbeitet als Apothekerin in Wien und ihre Leidenschaft sind pflanzliche Arzneimittel und deren Wirkung.

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