Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174

European Journal of Clinical Pharmacology
K M KaukonenP J Neuvonen

Abstract

Losartan is metabolised to its active metabolite E-3174 by CYP2C9 and CYP3A4 in vitro. Itraconazole is an inhibitor of CYP3A4, whereas fluconazole affects CYP2C9 more than CYP3A4. We wanted to study the possible interaction of these antimycotics with losartan in healthy volunteers. A randomised, double-blind, three-phase crossover study design was used. Eleven healthy volunteers ingested orally, once a day for 4 days, either itraconazole 200 mg, fluconazole (400 mg on day 1 and 200 mg on days 2-4) or placebo (control). On day 4, a single 50-mg oral dose of losartan was ingested. Plasma concentrations of losartan, E-3174, itraconazole, hydroxy-itraconazole and fluconazole were determined over 24 h. The blood pressure and heart rate were also recorded over 24 h. The mean peak plasma concentration (Cmax) and area under the curve [AUC(0-infinity)] of E-3174 were significantly decreased by fluconazole to 30% and to 47% of their control values, respectively, and the t1/2 was increased to 167%. Fluconazole caused only a nonsignificant increase (23-41%) in the AUC and t1/2 of the unchanged losartan. Itraconazole had no significant effect on the pharmacokinetic variables of losartan or E-3174. The ratio AUC(0-infinity)(E-3174)/AUC(0-inf...Continue Reading

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