FLUCONAZOLE BUT NOT ITRACONAZOLE DECREASES THE METABOLISM OF LOSARTANTO E-3174

Objective: Losartan is metabolised to its active metabolite E-3174 by CYP2C9 and CYP3A4 in vitro. Itraconazole is an inhibitor of CYP3A4, wh ereas fluconazole affects CYP2C9 more than CYP3A4. We wanted to study the possible interaction of these antimycotics with losartan in health y volunteers. Methods: A randomised, double-blind, three-phase crossov er study design was used. Eleven healthy volunteers ingested orally, o nce 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 sin gle 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. Results. The mean peak plasma concentration (C-ma x) and area under the curve [AUC(0-infinity)] of E-3174 were significa ntly decreased by fluconazole to 30% and to 47% of their control value s, respectively; and the t(1/2) was increased to 167%. Fluconazole cau sed only a nonsignificant increase (23-41%) in the AUC and tip of the unchanged losartan. Itraconazole had no significant effect on the phar macokinetic variables of losartan or E-3174. The ratio AUC(0-infinity) (E-3174)/AUC (0-infinity)(losartan) was 60% smaller during the flucona zole than during the placebo and itraconazole phases. No clinically si gnificant changes in the effects of losartan on blood pressure and hea rt rate were observed between fluconazole, itraconazole and placebo ph ases. Conclusion: Fluconazole but not itraconazole interacts with losa rtan by inhibiting its metabolism to the active metabolite E-3174. Thi s implicates that, in man, CYP2C9 is a major enzyme for the formation of E-3174 from losartan. The clinical significance of the fluconazole- losartan interaction is unclear, but the possibility of a decreased th erapeutic effect of losartan should be kept in mind.