The Influence of Single-Dose and Short-Term Administration of Quercetin on the Pharmacokinetics of Midazolam in Humans

ABSTRACT:Quercetin is a plant flavonol that is available from both daily diet and nutraceuticals. To investigate the effect of acute and short-term intake of high-dose quercetin on CYP3A-mediated metabolism, 10 healthy volunteers received 7.5 mg oral midazolam without, with a single dose of 1500 mg quercetin and after 1-week supplementation with 1500 mg quercetin daily. A substudy was performed in three subjects to explore the impact of repeated quercetin intake on intravenously administered midazolam. Coadministration with a single dose of quercetin did not significantly alter the pharmacokinetics of midazolam and its 1′-hydroxymetabolite, but following short-term quercetin intake, there was a trend to reduced midazolam exposure (geometric mean ratio of test–control area under the plasma concentration–time curve (AUC0 − ∞): 0.82; 90% confidence interval: 0.61–1.10) and midazolam–metabolite AUC0 − ∞ ratios were decreased by 9.7%–47.6% from control in seven subjects. The tendency was opposite when midazolam was given intravenously. We conclude that a single dose of quercetin would not provoke any toxic adverse events when coadministered with midazolam, whereas repeated quercetin intake can reduce systemic exposure to the orally given drug by increasing its CYP3A-catalyzed metabolism. As the effect deviated after intravenous drug administration, different mechanisms of interaction may be involved at the intestinal site compared with the liver. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3199–3207, 2015