Effect of fluconazole on plasma fluvastatin and pravastatin concentrations

Objective: To study the effects of fluconazole on the pharmacokinetics of f luvastatin and pravastatin, two inhibitors of 3-hydroxy-3-methylglutaryl-co enzyme A (HMG-CoA) reductase. Methods: Two separate randomised, double-blind, two-phase, crossover studie s with identical study design were carried out. In each study, 12 healthy v olunteers 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 sche dule. 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 fl uvastatin, pravastatin and fluconazole were measured over 24 h. Results: In study I, fluconazole increased the mean area under the plasma f luvastatin concentration-time curve (AUC(0-infinity)) by 84% (P < 0.01), th e mean elimination half-life (t(1/2)) of fluvastatin by 80% (P < 0.01) and its mean peak plasma concentration (C-max) by 44% (P < 0.05). In study II, fluconazole had no significant effect on the pharmacokinetics of pravastati n. Conclusions: Fluconazole has a significant interaction with fluvastatin. Th e mechanism of the increased plasma concentrations and prolonged eliminatio n of fluvastatin is probably inhibition of the CYP2C9-mediated metabolism o f fluvastatin by fluconazole. Care should be taken if fluconazole or other potent inhibitors of CYP2C9 are prescribed to patients using fluvastatin. H owever, pravastatin is not susceptible to interactions with fluconazole or other potent CYP2C9 inhibitors.