Phytic acid enhances the oral absorption of isorhamnetin, quercetin, and kaempferol in total flavones of Hippophae rhamnoides L.
OBJECTIVE
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 (IP6) 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 IP6. The aqueous solubility and lipophilicity of isorhamnetin, quercetin, and kaempferol were determined with and without IP6, and mucosal epithelial damage resulting from IP6 addition was evaluated by MTT assays and morphology observations.


RESULTS
The Papp of isorhamnetin, kaempferol, and quercetin was improved 2.03-, 1.69-, and 2.11-fold in the presence of 333 μg/mL of IP6, respectively. Water solubility was increased 22.75-, 15.15-, and 12.86-fold for isorhamnetin, kaempferol, and quercetin, respectively, in the presence of 20mg/mL IP6. The lipophilicity of the three flavonoids was slightly decreased, but their hydrophilicity was increased after the addition of IP6 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 IP6 (200 mg/kg) in rats. In addition, IP6 (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 IP6. The main mechanisms are related to their enhanced aqueous solubility and permeability in the presence of IP6. In summary, IP6 is a potential absorption enhancer for pharmaceutical formulations that is both effective and safe.
Research Center for Health and Nutrition, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: rosexie_1996@hotmail.com.
Yan
Y
Xie
Teaching and Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Huilin
H
Luo
Research Center for Health and Nutrition, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Jingze
J
Duan
Research Center for Health and Nutrition, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Chao
C
Hong
Global Pharmaceutical Research and Development, Hospira Inc., 1776 North Centennial Drive, McPherson, KS 67460, USA.
Ping
P
Ma
Pharmacy Department, Shanghai TCM-Integrated Hospital, Shanghai 200082, China. Electronic address: lgwshutcm@163.com.
Guowen
G
Li
Teaching and Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Tong
T
Zhang
Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Tao
T
Wu
Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Guang
G
Ji
D000284:Administration, Oral; D000327:Adsorption; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D004353:Drug Evaluation, Preclinical; D031281:Hippophae; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects; D044949:Kaempferols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D010833:Phytic Acid / Q000494:pharmacology*; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011794:Quercetin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D044949:Kaempferols; D010936:Plant Extracts; C047368:3-methylquercetin; D010833:Phytic Acid; D011794:Quercetin
Absorption enhancer; Flavonoids; Oral absorption; Permeability; Phytic acid; Solubility