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

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   μg/mL of 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 IP 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 2.39   ±   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   μg/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 6 . In summary, IP 6 is a potential absorption enhancer for pharmaceutical formulations that is both effective and safe.