METABOLISM-BASED DRUG INTERACTIONS INVOLVING ORAL AZOLE ANTIFUNGALS IN HUMANS

The introduction of ketoconazole into medical practice in the early 1970s initiated a new era of systemic antifungal therapy. The availability of an orally absorbed drug with low toxicity permitted outpatient therapy of deep mycoses, long-term prophylaxis of immunocompromised patients, and treatment...

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Bibliographic Details
Published in:Drug metabolism reviews 1999-01, Vol.31 (3), p.665-717
Main Authors: BENEDETTI, M. STROLIN, BANI, M.
Format: Article
Language:English
Subjects:
Adjuvants, Immunologic - pharmacology
Anti-Asthmatic Agents - pharmacology
Anti-Infective Agents - pharmacology
Antibiotics. Antiinfectious agents. Antiparasitic agents
Anticoagulants - pharmacology
Antifungal agents
Antifungal Agents - pharmacology
Antineoplastic Agents - pharmacology
Antiprotozoal Agents - pharmacology
Azoles - pharmacology
Biological and medical sciences
Cardiovascular Agents - pharmacology
Central Nervous System Agents - pharmacology
Drug Interactions
Gastrointestinal Agents - pharmacology
Humans
Hypoglycemic Agents - pharmacology
Medical sciences
Pharmacology. Drug treatments
Renal Agents - pharmacology
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Summary:The introduction of ketoconazole into medical practice in the early 1970s initiated a new era of systemic antifungal therapy. The availability of an orally absorbed drug with low toxicity permitted outpatient therapy of deep mycoses, long-term prophylaxis of immunocompromised patients, and treatment of low-morbidity conditions. All three options had been unattractive when the only systemic therapy available was the intravenous administration of amphotericin B, a rather toxic drug whose mechanism of action consists in binding irreversibly to ergosterol, an essential component of fungal cell membranes. Subsequently, newer azole antifungals have largely replaced ketoconazole, and future azoles may expand the antifungal spectrum further. The mechanism of action of both azole and allylamine (e.g., terbinafine) antimycotics consists in blocking the ergosterol synthesis, leading to the alteration of fungal membrane fluidity and, consequently, inhibition of cell growth and replication. Azoles interfere with the conversion of lanosterol to ergosterol by inhibiting a fungal cytochrome P450 enzyme, lanosterol 14-demethylase, whereas terbinafine exhibits a strong inhibition of a non-cytochrome P450 enzyme, squalene epoxidase.
ISSN:0360-2532
1097-9883
DOI:10.1081/DMR-100101941