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

Objective: Losartan is metabolised to its active metabolite E-3174 by CYP2C9 and CYP3A4 in vitro. Itraconazole is an inhibitor of CYP3A4, whereas ̄uconazole a€ects CYP2C9 more than CYP3A4. We wanted to study the possible interaction of these antimycotics with losartan in healthy volunteers. Methods: 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, ̄uconazole (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 ̄uconazole were determined over 24 h. The blood pressure and heart rate were also recorded over 24 h. Results: The mean peak plasma concentration (Cmax) and area under the curve [AUC…0±1†] of E-3174 were signi®cantly decreased by ̄uconazole to 30% and to 47% of their control values, respectively, and the t1/2 was increased to 167%. Fluconazole caused only a nonsigni®cant increase (23±41%) in the AUC and t1/2 of the unchanged losartan. Itraconazole had no signi®cant e€ect on the pharmacokinetic variables of losartan or E-3174. The ratio AUC…0±1)E-3174/AUC…0±1†losartan was 60% smaller during the ̄uconazole than during the placebo and itraconazole phases. No clinically signi®cant changes in the e€ects of losartan on blood pressure and heart rate were observed between ̄uconazole, itraconazole and placebo phases. Conclusion: Fluconazole but not itraconazole interacts with losartan by inhibiting its metabolism to the active metabolite E-3174. This implicates that, in man, CYP2C9 is a major enzyme for the formation of E-3174 from losartan. The clinical signi®cance of the ̄uconazole±losartan interaction is unclear, but the possibility of a decreased therapeutic e€ect of losartan should be kept in mind.