Enhanced oral bioavailability of docetaxel in rats combined with myricetin: In situ and in vivo evidences

The purpose of this study was to investigate the effect of myricetin on the pharmacokinetics of docetaxel in rats. In comparison to oral docetaxel alone (40 mg/kg), the bioavailability of docetaxel could be significantly enhanced by 1.6-2.4-fold via oral co-administration with various flavonoids (apigenin, naringenin, baicalein, quercetin and myricetin) at a dosage of 10 mg/kg, and myricetin showed the highest bioavailability improvement. Further pharmacokinetic studies demonstrated that the presence of myricetin (5-20 mg/kg) enhanced both C-max and AUC of docetaxel with the highest C-max (162 ng/mL, 2.3-fold) and relative bioavailability (244%) achieved at 10 mg/kg of myricetin, while t(1/2) was not influenced. In order to explore the reasons for such bioavailability enhancement of docetaxel, rat in situ single-pass intestinal perfusion model and intravenous docetaxel co-administrated with oral myricetin were carried out. After combining with myricetin, the permeability coefficient (P-blood) of docetaxel based on its appearance in mesenteric blood was significantly increased up to 3.5-fold in comparison to that of docetaxel alone. Different from oral docetaxel, the intravenous pharmacokinetics of docetaxel was not affected by co-administration of myricetin, indicating the limited effect of myricetin on the elimination of docetaxel. The above findings suggested that the oral bioavailability enhancement of docetaxel via co-administration with myricetin might be mainly attributed to the enhanced absorption in gastrointestinal tract rather than modulating the elimination of docetaxel. (C) 2017 Elsevier B.V. All rights reserved.