Effect of fluconazole on plasma fluvastatin and pravastatin concentrations.
OBJECTIVE
To study the effects of fluconazole on the pharmacokinetics of fluvastatin and pravastatin, two inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.


METHODS
Two separate randomised, double-blind, two-phase, crossover studies with identical study design were carried out. In each study, 12 healthy volunteers were given a 4-day pretreatment with oral fluconazole (400 mg on day 1 and 200 mg on days 2-4) or placebo, according to a randomisation schedule. On day 4, a single oral dose of 40 mg fluvastatin (study I) or 40 mg pravastatin (study II) was administered orally. Plasma concentrations of fluvastatin, pravastatin and fluconazole were measured over 24 h.


RESULTS
In study 1, fluconazole increased the mean area under the plasma fluvastatin concentration-time curve (AUC0-infinity) by 84% (P < 0.01), the mean elimination half-life (t1/2) of fluvastatin by 80% (P < 0.01) and its mean peak plasma concentration (Cmax) by 44% (P < 0.05). In study II, fluconazole had no significant effect on the pharmacokinetics of pravastatin.


CONCLUSIONS
Fluconazole has a significant interaction with fluvastatin. The mechanism of the increased plasma concentrations and prolonged elimination of fluvastatin is probably inhibition of the CYP2C9-mediated metabolism of fluvastatin by fluconazole. Care should be taken if fluconazole or other potent inhibitors of CYP2C9 are prescribed to patients using fluvastatin. However, pravastatin is not susceptible to interactions with fluconazole or other potent CYP2C9 inhibitors.
Kantola
T
T
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Backman
J T
JT
Niemi
M
M
Kivistö
K T
KT
Neuvonen
P J
PJ
D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004311:Double-Blind Method; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000097:blood*; D005260:Female; D015725:Fluconazole / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood*; D007211:Indoles / Q000097:blood*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000502:physiology; D017035:Pravastatin / Q000097:blood*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000502:physiology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; 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; D017035:Pravastatin