title: Enhanced oral bioavailability of docetaxel in rats combined with myricetin: In situ and in vivo evidences.
abstract: 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 (40mg/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 10mg/kg, and myricetin showed the highest bioavailability improvement. Further pharmacokinetic studies demonstrated that the presence of myricetin (5-20mg/kg) enhanced both Cmaxand AUC of docetaxel with the highest Cmax(162ng/mL, 2.3-fold) and relative bioavailability (244%) achieved at 10mg/kg of myricetin, while t1/2was 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 (Pblood) 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.
authors.affiliation: School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Tianyun
authors.initials: T
authors.lastname: Hao
authors.affiliation: School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yunni
authors.initials: Y
authors.lastname: Ling
authors.affiliation: School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Wu
authors.affiliation: School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Shen
authors.affiliation: School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Liang
authors.affiliation: School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: newgaoyuan@163.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: silence_qs@163.com.
authors.forename: Shuai
authors.initials: S
authors.lastname: Qian
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D000077143:Docetaxel; D004347:Drug Interactions; D005419:Flavonoids / Q000494:pharmacology*; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D005419:Flavonoids; D043823:Taxoids; D000077143:Docetaxel; C040015:myricetin
keywords: Bioavailability; Docetaxel; Myricetin; Permeability