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Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam
J Ahonen1, K T Olkkola, P J Neuvonen
1Department of Anaesthesia, Helsinki University Central Hospital, Finland.
Objective:
Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam.
Methods:
A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, alpha-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h.
Results:
Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC0-3, AUC0-17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (Cmax) 2- to 2.5-fold compared with placebo. The AUC0-3 and the Cmax of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases.
Conclusion:
We conclude that the metabolism of orally administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole.
Insights
Oral fluconazole more significantly impacts midazolam metabolism than intravenous administration. This interaction affects drug absorption and elimination, highlighting the importance of administration route in drug metabolism studies.
Area of Science:
- Pharmacology
- Drug Metabolism
- Clinical Pharmacy
Background:
- Midazolam, a short-acting benzodiazepine hypnotic, is primarily metabolized by the CYP3A4 enzyme.
- Azole antimycotics, such as fluconazole, are known to inhibit CYP3A4 activity.
- Concomitant use of oral fluconazole and oral midazolam can alter midazolam's pharmacokinetic and pharmacodynamic profiles.
Purpose of the Study:
- To compare the effects of oral versus intravenous fluconazole administration on the pharmacokinetics and pharmacodynamics of orally ingested midazolam.
- To investigate the influence of fluconazole's administration route on midazolam metabolism and its clinical effects.
Main Methods:
- A double-dummy, randomized, cross-over study involving 9 healthy volunteers.
- Three study phases: oral fluconazole with IV placebo, IV fluconazole with oral placebo, and oral placebo with IV placebo.
- Volunteers received oral midazolam 60 minutes after fluconazole or placebo administration; plasma concentrations and pharmacodynamic effects were monitored for 17 hours.
Main Results:
- Both oral and intravenous fluconazole significantly increased midazolam's area under the curve (AUC) by 2-3 fold and its elimination half-life by 2.5 fold.
- Midazolam's peak concentration (Cmax) increased 2-2.5 fold with both fluconazole administration routes.
- Higher midazolam AUC and Cmax were observed following oral fluconazole compared to intravenous fluconazole.
- Both routes of fluconazole administration enhanced midazolam's pharmacodynamic effects, with no significant difference between the two fluconazole phases.
Conclusions:
- Oral administration of fluconazole resulted in a more pronounced inhibition of oral midazolam metabolism compared to intravenous administration.
- The route of fluconazole administration is a critical factor influencing the interaction with orally administered midazolam.
- These findings have implications for managing drug-drug interactions involving CYP3A4 substrates and azole antifungals.