Phytic acid enhances the oral absorption of isorhamnetin, quercetin, and kaempferol in total flavones of Hippophae rhamnoides L.

摘要

Aim: Total flavones of Hippophae rhamnoides L. (TFH) have a clinical use in the treatment of cardiac disease. The pharmacological effects of TFH are attributed to its major flavonoid components, isorhamnetin, kaempferol, and quercetin. However, poor oral bioavailability of these flavonoids limits the clinical applications of TFH. This study explores phytic acid (IP_6) enhancement of the oral absorption in rats of isorhamnetin, kaempferol, and quercetin in TFH.Methods: In vitro Caco-2 cell experiments and in vivo pharmacokinetic studies were performed to investigate the effects of IP_6. The aqueous solubility and lipophilicity of isorhamnetin, quercetin, and kaempferol were determined with and without IP_6, and mucosal epithelial damage resulting from IP_6 addition was evaluated by MTT assays and morphology observations. Results: The P_(app) of isorhamnetin, kaempferol, and quercetin was improved 2.03-, 1.69-, and 2.11-fold in the presence of 333 mug/mLof IP_6, respectively. Water solubility was increased 22.75-, 15.15-, and 12.86-fold for isorhamnetin, kaempferol, and quercetin, respectively, in the presence of 20 mg/mL 1P_6. The lipophilicity of the three flavonoids was slightly decreased, but their hydrophilicity was increased after the addition of IP_6 in the water phase as the logP values of isorhamnetin, kaempferol, and quercetin decreased from 2.38 ± 0.12 to 1.64 ± 0.02, from 2.57 ± 0.20 to 2.01 ± 0.04, and from 239 ± 0.12 to 1.15 ± 0.01, respectively. The absorption enhancement ratios were 3.21 for isorhamnetin, 2.98 for kaempferol, and 1.64 for quercetin with co-administration of IP_6 (200 mg/kg) in rats. In addition, IP_6 (200 mg/kg, oral) caused neither significant irritation to the rat intestines nor cytotoxicity (400 mug/mL) in Caco-2 cells. Conclusions: The oral bioavailability of isorhamnetin, kaempferol, and quercetin in TFH was enhanced by the co-administration of IP_6. The main mechanisms are related to their enhanced aqueous solubility and permeability in the presence of IP_5. In summary, IP_6 is a potential absorption enhancer for pharmaceutical formulations that is both effective and safe.