EFFECT OF FLUCONAZOLE ON THE PHARMACOKINETICS OF EPROSARTAN AND LOSARTAN IN HEALTHY MALE-VOLUNTEERS

Objective: To investigate the effect of steady-state fluconazole admin istration on the disposition of eprosartan, losartan, and E-3174. Meth ods: Sixteen healthy male subjects received 300 mg eprosartan every 12 hours, and 16 received 100 mg losartan every 24 hours on study days 1 to 20, All 32 subjects received 200 mg fluconazole every 24 hours beg inning on day 11 and continuing through day 20. Serial blood samples w ere collected over one dosing interval on study days 10 and 20 for mea surement of plasma concentrations of eprosartan, losartan, and E-3174 (the active metabolite of losartan). Results: There was no significant difference in eprosartan area under the concentration-time curve from time 0 to time of last quantifiable concentration [AUC(0-t)] or maxim um concentration (C-max) when administered alone and with fluconazole, After concomitant administration with fluconazole, losartan AUC(0-t) and C-max were significantly increased 66% and 30%, respectively, comp ared with those values for losartan alone, The AUC(0-t) and C-max for E-3174 were significantly decreased 43% and 56%, respectively, after a dministration of losartan with fluconazole. Conclusions: Fluconazole s ignificantly increases the steady-state AUC of losartan and inhibits t he formation of the active metabolite of losartan, E-3174, In contrast , fluconazole administration has no effect on the steady-state pharmac okinetics of eprosartan.