Effect of fluconazole on the pharmacokinetics of eprosartan and losartan in healthy male volunteers.
OBJECTIVE
To investigate the effect of steady-state fluconazole administration on the disposition of eprosartan, losartan, and E-3174.


METHODS
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 beginning on day 11 and continuing through day 20. Serial blood samples were collected over one dosing interval on study days 10 and 20 for measurement 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 maximum concentration (Cmax) when administered alone and with fluconazole. After concomitant administration with fluconazole, losartan AUC(0-t) and Cmax were significantly increased 66% and 30%, respectively, compared with those values for losartan alone. The AUC(0-t) and Cmax for E-3174 were significantly decreased 43% and 56%, respectively, after administration of losartan with fluconazole.


CONCLUSIONS
Fluconazole significantly increases the steady-state AUC of losartan and inhibits the formation of the active metabolite of losartan, E-3174. In contrast, fluconazole administration has no effect on the steady-state pharmacokinetics of eprosartan.
Kazierad
D J
DJ
Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, Buffalo, N.Y., USA.
Martin
D E
DE
Blum
R A
RA
Tenero
D M
DM
Ilson
B
B
Boike
S C
SC
Etheredge
R
R
Jorkasky
D K
DK
D000179:Acrylates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004334:Drug Administration Schedule; D015725:Fluconazole / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019808:Losartan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000187:drug effects / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013876:Thiophenes; D013997:Time Factors
D000179:Acrylates; D000935:Antifungal Agents; D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; D013876:Thiophenes; C068373:eprosartan; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; C066026:losartan carboxylic acid; D019808:Losartan