The cytochrome P450 3A4 inhibitor itraconazole markedly increases the plasma concentrations of dexamethasone and enhances its adrenal-suppressant effect.
OBJECTIVE
To examine the possible interaction of itraconazole with orally and intravenously administered dexamethasone.


METHODS
In a randomized, double-blind, placebo-controlled crossover study with four phases, eight healthy subjects took either 200 mg itraconazole (in two phases) or placebo (in two phases) orally once daily for 4 days. On day 4 each subject received an oral dose of 4.5 mg dexamethasone or an intravenous dose of 5.0 mg dexamethasone sodium phosphate during both itraconazole and placebo phases. Plasma dexamethasone and cortisol concentrations were determined by HPLC up to 71 hours, itraconazole and hydroxyitraconazole up to 23 hours.


RESULTS
Itraconazole decreased the systemic clearance of intravenously administered dexamethasone by 68% (P < .001), increased the total area under the plasma dexamethasone concentration-time curve [AUC(0-infinity)] 3.3-fold (P < .001), and prolonged the elimination half-life of dexamethasone 3.2-fold (P < .001). The AUC(0-infinity) of oral dexamethasone was increased 3.7-fold (P < .001), the peak plasma concentration 1.7-fold (P < .001), and the elimination half-life 2.8-fold (P < .001) by itraconazole. The morning plasma cortisol concentrations measured 47 and 71 hours after administration of dexamethasone were substantially lower after exposure to itraconazole than to placebo (P < .001). Accordingly, the adrenal-suppressant effect of dexamethasone was greatly enhanced during the itraconazole phases.


CONCLUSIONS
Itraconazole markedly increases the systemic exposure to and effects of dexamethasone. A careful follow-up is recommended when itraconazole or other potent inhibitors of the cytochrome P450 3A4 are added to the drug regimen of patients receiving dexamethasone.
Varis
T
T
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Kivistö
K T
KT
Backman
J T
JT
Neuvonen
P J
PJ
D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003907:Dexamethasone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007275:Injections, Intravenous; D017964:Itraconazole / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*
D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D005938:Glucocorticoids; D017964:Itraconazole; D003907:Dexamethasone; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D006854:Hydrocortisone