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 fluconazole affects 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, 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.


RESULTS
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-infinity)losartan was 60% smaller during the fluconazole than during the placebo and itraconazole phases. No clinically significant changes in the effects of losartan on blood pressure and heart rate were observed between fluconazole, itraconazole and placebo phases.


CONCLUSIONS
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 significance of the fluconazole losartan interaction is unclear, but the possibility of a decreased therapeutic effect of losartan should be kept in mind.
Kaukonen
K M
KM
Department of Clinical Pharmacology, University of Helsinki, Finland. maija.jalava@helsinki.fi
Olkkola
K T
KT
Neuvonen
P J
PJ
D000328:Adult; D000935:Antifungal Agents / Q000097:blood / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics*; D017964:Itraconazole / Q000097:blood / Q000494:pharmacology*; D019808:Losartan / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D012016:Reference Values; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D000959:Antihypertensive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D013777:Tetrazoles; D017964:Itraconazole; D015725:Fluconazole; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D039181:Steroid 16-alpha-Hydroxylase; C510163:CYP3A4 protein, human; C066026:losartan carboxylic acid; D019808:Losartan