Imidazole antifungal — inhibits fungal CYP51 ergosterol synthesis. Potent CYP3A4 inhibitor in human liver — historically the gold-standard "strong CYP3A4 perpetrator" for DDI studies. Oral use restricted by FDA 2013 to mycoses unresponsive to alternatives due to hepatotoxicity + adrenal suppression.
Half-Life (t½)
PO: 7.7h
Dosing Guidelines
PO: Typical 200 mg (Range: 200–400 mg)
Target Organ Systems
endocrine
digestive
immune-hematologic
Interactions
Cyclosporine (major): CYP3A4 inhibition. Gomez 1995 (PMID:7628178): ketoconazole 200 mg/d raised cyclosporine oral F from 22% to 56% and reduced IV CL from 0.32 to 0.18 L/h/kg (n=5 healthy crossover). Combined effect ~4.5× cyclosporine AUC.
Midazolam (major): CYP3A4 inhibition. Olkkola 1994 (PMID:8181191): ketoconazole 400 mg/d × 4 d raised midazolam AUC 10-15× and Cmax 3-4× (n=9 healthy). Avoid combination; if essential, drastically reduce midazolam dose.
Triazolam (major): Ketoconazole is a potent CYP3A4 inhibitor. Greenblatt 2011 (PMID:21235585) reports verbatim Ki 0.011-0.045 µM in human liver microsomes covering triazolam α- and 4-hydroxylation, midazolam α-OH, testosterone 6β-OH, and nifedipine oxidation, mixed competitive-noncompetitive mechanism. Ki used here is 0.015 µM (textbook midpoint of the verbatim range).
Alprazolam (major): von Moltke 1994 (PMID:7946933) verbatim: "Ketoconazole was a potent inhibitor of ALP metabolism in vitro (Ki = 0.046 microM)". HLM, alprazolam 4-hydroxylation as marker.
Sildenafil (major): Warrington 2000 (PMID:10725306) verbatim: "Sildenafil biotransformation (36 microM) was inhibited by increasing concentrations of ketoconazole and ritonavir (IC(50) values less than 0.02 microM)". HLM, sildenafil → UK-103,320 (N-demethylation). Ki used is 0.015 µM (midpoint of the <0.02 bound).
Nifedipine (warn): Greenblatt 2011 (PMID:21235585) covers nifedipine oxidation alongside triazolam in the same Ki range 0.011-0.045 µM (HLM, mixed competitive-noncompetitive). Ki used is 0.015 µM (midpoint).