Intestinal Absorption Barricade Network And The Effect Of Apigenin Influencing Bioavailability Of Raloxifene

Intestinal absorption barricade network can prevent the absorption of the toxicant and antigenic, and also be the majoy factor of limiting the absorption of the drug, what is leading to the low bioavailability of drugs. At the same time, it may be the basic reason of why the selection compounds having better bioactive could not gain further study.Flavonoid is a kind of phytoestrogen, have estrogen activity, generally exist in natural herbal and our diet. It participates metabolic activity of enzymes and transport of transporters, has great regulation to Intestinal absorption barricade network. Raloxifene is a selective estrogen receptor modulators (SERM), is commonly used in curing breast carcinoma and osteoporosis, but its absolute bioavailability is very low. Its poor bioavailability is thought to be the result of extensive phase II metabolism. Flavone shows the similar absorb and metabolic pathway with raloxifene. Bith have similar curative effect and limited by Intestinal absorption barricade network too. Researchers have shown that two kinds of flavonoids, apigenin and genistein conld influence raloxifene cycling intestine by inhibit its II phase metabolism. We will study the effec between flavonoids and drug transporter or drug-metabolizing enzyme in order to elucidate how flavonoids inhibit II phase metabolism of raloxifene. We former optimize the compatibility of raloxifene and flavonoid, through reasonable compatibility, raise the bioavailability and clinical curative effect of raloxifene.To investigate the influence of the combination on the pharmacokinetics of raloxifene, the rat was selected as major object and apigenin as the medication for combination, studied the pharmacokinetics of raloxifene when in combination with apigenin on the base of the pharmacokinetics of raloxifene when raloxifene was dosed to rats alone, and revealed the influence of the combination on the pharmacokinetics of raloxifene in rats.The high-perfonmance liquid chromatography(HPLC)with UV detection was developed for quantifying the concentration of raloxifene in intestine perfusing solution, plasma, bile, excreta and other biological samples .The calibration curve of raloxifene in biological sample was linear in the range from1.7 to 26.7μg·mL^-1, with r=0.9994, and the LOQ of raloxifene was about 1 ng .The extraction recoverise of raloxifene and apigenin in all samples were over 80%, the relative standard deviations of within-day and between-day of raloxifene were lower than 7%.This method was simple,rapid and accurate enough to be used in this pharmacokinetic study To explore the intestinal absorption characters of raloxifene and the factors affecting absorption of raloxifene, the changes of the absorption of raloxifene when in combination with apigenin by utilizing the rat intestinal recirculating method in situ .The intestine absorption of raloxifene was pH-dependant andconcentration-dependent (P<0.05),but there was no site specific absorption in various intestinal segments (duodenumjejunum, ileum and colon)( P>0.05), which suggested that the intestinal absorption of raloxifene was via the passive transport mechanism; apigenin restrained the absorption of raloxifene from the intestine(P<0.05), and the absorption ratio increased significantly (P<0.05).To investigate the absorption kinetics of raloxifene in rats by utilizing the catheterization of the jugular vein of rats when raloxifene was araloxifeneinistered alone or in combination with apigenin .The absolute bioavailability (FMS) of oral araloxifeneinistration of raloxifene was about 2.8%;The concentration-time process of raloxifene after i.v. fitted two-compartment open model,while raloxifenewas orally administered to rats, all fit in two -compartment open model, and were in according with linear kinetics; When in combination with apigenin, the plasma concentration, Cmax , AUC_0-∞, ke and F of raloxifene were higher than those when raloxifene was inistered alone(P<0.05), T_1/2β was higher than those when raloxifene was administered alone (P<0.05), the degree of the changes were associated with the dosage of apigenin,and the concentration-time process still accorded with two-compartment open model.Taken together, wo considered that, administration combining with apigenin, concentration of raloxifene in plasma has raised, and the absorption and bioavailability have raised too. It offered a reliable matter for intestinal absorption barricade network.