title: Mechanism of enhanced oral absorption of morin by phospholipid complex based self-nanoemulsifying drug delivery system.
abstract: Phospholipid complex (PLC) based self-nanoemulsifying drug delivery system (PLC-SNEDDS) has been developed for efficient delivery of drugs with poor solubility and low permeability. In the present study, a BCS class IV drug and a P-glycoprotein (P-gp) substrate, morin, was selected as the model drug to elucidate the oral absorption mechanism of PLC-SNEDDS. PLC-SNEDDS was superior to PLC in protecting morin from degradation by intestinal enzymes in vitro. In situ perfusion study showed increased intestinal permeability by PLC was duodenum-specific. In contrast, PLC-SNEDDS increased morin permeability in all intestinal segments and induced a change in the main absorption site of morin from colon to ileum. Moreover, ileum conducted the lymphatic transport of PLC-SNEDDS, which was proven by microscopic intestinal visualization of Nile red labeled PLC-SNEDDS and lymph fluids in vivo. Low cytotoxicity and increased Caco-2 cell uptake suggested a safe and efficient delivery of PLC-SNEDDS. The increased membrane fluidity and disrupted actin filaments were closely associated with the increased cell uptake of PLC-SNEDDS. PLC-SNEDDS could be internalized into enterocytes as an intact form in a cholesterol-dependent manner via clathrin-mediated endocytosis and macropinocytosis. The enhanced oral absorption of morin was attributed to the P-gp inhibition by Cremophor RH and the intact internalization of M-PLC-SNEDDS into Caco-2 cells bypassing P-gp recognition. Our findings thus provide new insights into the development of novel nanoemulsions for poorly absorbed drugs.
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, Sichuan University , No. 17. Section 3, Southern Renmin Road, Chengdu 610041, People's Republic of China.
authors.forename: Jinjie
authors.initials: J
authors.lastname: Zhang
authors.forename: Jianbo
authors.initials: J
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ju
authors.forename: Yao
authors.initials: Y
authors.lastname: Fu
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002470:Cell Survival; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions / Q000737:chemistry*; D005419:Flavonoids / Q000008:administration & dosage*; D006801:Humans; D007408:Intestinal Absorption; D008962:Models, Theoretical; D010743:Phospholipids / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D047309:Flavones
chemical_list: D004337:Drug Carriers; D004655:Emulsions; D005419:Flavonoids; D010743:Phospholipids; C008548:morin; D047309:Flavones
keywords: Caco-2 cells; intestinal absorption; mechanism; morin; phospholipid complex; self-nanoemulsifying