title: Absorption Mechanism of a Physical Complex of Monomeric Insulin and Deoxycholyl-l-lysyl-methylester in the Small Intestine.
abstract: Currently, oral administration of insulin still remains the best option to avoid the burden of repeated subcutaneous injections and to improve its pharmacokinetics. The objective of the present investigation was to demonstrate the absorption mechanism of insulin in the physical complexation of deoxycholyl-l-lysyl-methylester (DCK) for oral delivery. The oral insulin/DCK complex was prepared by making a physical complex of insulin aspart with DCK through ion-pair interaction in water. For the cellular uptake study, fluorescein-labeled insulin or DCK were prepared according to a standard protocol and applied to Caco-2 or MDCK cell lines. For the PK/PD studies, we performed intrajejunal administration of different formulation of insulin/DCK complex to diabetic rats. The resulting insulin and DCK complex demonstrated greatly enhanced lipophilicity as well as increased permeation across Caco-2 monolayers. The immunofluorescence study revealed the distribution of the complex in the cytoplasm of Caco-2 cells. Moreover, in the apical sodium bile acid transporter (ASBT) transfected MDCK, the insulin/DCK complex showed interaction with ASBT, and also demonstrated absorption through passive diffusion. We could not find that any evidence of endocytosis in relation to the uptake of insulin complex in vitro. In the rat intestine model, the highest absorption of insulin complex was observed in the jejunum at 1 h and then in the ileum at 2-4 h. In PK/PD study, the complex showed a similar PK profile to that of SC insulin. Overall, the study showed that the effect of DCK on enhancing the absorption of insulin resulted from transcellular processes as well as bile acid transporter activity.
authors.affiliation: †Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Foyez
authors.initials: F
authors.lastname: Mahmud
authors.affiliation: †Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Ok-Cheol
authors.initials: OC
authors.lastname: Jeon
authors.affiliation: ‡Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Taslim A
authors.initials: TA
authors.lastname: Al-Hilal
authors.affiliation: †Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Seho
authors.initials: S
authors.lastname: Kweon
authors.affiliation: †Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea.|§Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, United States.
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yang
authors.affiliation: †Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea.|∥Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 110-744, South Korea.
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Lee
authors.affiliation: †Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea.|‡Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007328:Insulin / Q000737:chemistry* / Q000493:pharmacokinetics; D007421:Intestine, Small / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004337:Drug Carriers; D007328:Insulin; C504125:deoxycholyl-L-lysyl-methylester; D002635:Chenodeoxycholic Acid; D008239:Lysine
keywords: bile acid; enhancer; insulin; oral absorption; physical complex; tight junction