Interaction between fluconazole and midazolam in intensive care patients.
BACKGROUND
Midazolam is used for sedation of intensive care unit (ICU) patients and it is extensively metabolised by CYP3A4 enzymes. The antimycotic fluconazole is often used in these patients as well and has been shown to inhibit CYP3A4-mediated drug metabolism.


METHODS
In a study of the effect of fluconazole on midazolam in the ICU, ten mechanically ventilated patients (age 29 to 61 years, 8 male) sedated with a stable midazolam infusion were enrolled after a decision to start fluconazole treatment. Fluconazole was infused for 30 min at intervals of 24 h, with an initial dose of 400 mg and following doses of 200 mg. The midazolam infusion rate remained unchanged during the study period of 48 h. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and alpha-hydroxymidazolam conjugate were determined at baseline, and at 6, 12, 18, 24, 36, and at 48 h thereafter.


RESULTS
Concentrations of midazolam were significantly increased (range 0 to 4-fold, P < 0.05) after start of fluconazole treatment. These increases were most marked in patients with renal failure. During the study period, the ratio of alpha-hydroxymidazolam to midazolam decreased progressively (P < 0.05).


CONCLUSIONS
In ICU patients receiving fluconazole, reduction of midazolam infusion rate should be considered if the degree of sedation is found to be increasing.
Ahonen
J
J
Department of Anaesthesia, University of Helsinki, Finland.
Olkkola
K T
KT
Takala
A
A
Neuvonen
P J
PJ
D000328:Adult; D000704:Analysis of Variance; D000935:Antifungal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003422:Critical Care; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011175:Positive-Pressure Respiration; D051437:Renal Insufficiency / Q000097:blood
D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; C040081:1-hydroxymethylmidazolam; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam