title: Diabetes correction in pancreatectomized canines by orally absorbable insulin-deoxycholate complex.
abstract: Oral insulin therapy has great potential benefits over conventional therapy for diabetic patients as well as mimicking the physiological fate of insulin. Here we evaluated the characteristics of insulin and deoxycholate-based synthetic N(alpha)-deoxycholyl-L-lysyl-methylester (DCK) complex, and diabetes correction in pancreatectomized canines after oral administration. After the insulin/DCK complexation was made, the insulin's folding structure, stability against digestive enzymes, lipophilicity and permeability to Caco-2 monolayer were evaluated in vitro. Diabetic canines were kept under fasting conditions, and Eudragit-coated gelatin capsules containing insulin or insulin/DCK powder were singly or triply administered. Evaluation of glucodynamics, pharmacokinetics, oral glucose tolerance test (OGTT) and reproducibility were carried out. After complexation with DCK, the folding structure of insulin did not become denatured and the resistance against digestive enzymes was powerfully improved. The lipophilicity and permeability of insulin/DCK (coupling ratio up to 1:10) were also highly increased. The insulin/DCK complex, administered orally into diabetic canines at the doses of 21, 42, and 81 IU/kg, reduced the plasma glucose levels by about 28%, 44% and 67%, respectively, while the plasma insulin concentrations increased. During OGTT, insulin/DCK nearly maintained the normoglycemic state in the diabetic canines, whereas the hyperglycemic state of placebo-treated controls was not corrected. During oral administration of insulin/DCK, it repetitively showed similar therapeutic efficacy in diabetic canines for 3 days. The therapeutic efficacy of insulin/DCK was exhibited in its digestive enzyme resistance, deoxycholate-based lipophilicity for enhancing permeability and intact insulin delivery without chemical modification, providing potential oral therapeutic remedy as an alternative to injectable insulin medication.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Sang Kyoon
authors.initials: SK
authors.lastname: Kim
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
authors.forename: Sunji
authors.initials: S
authors.lastname: Jin
authors.forename: Hyun Tae
authors.initials: HT
authors.lastname: Moon
authors.forename: Ok Cheol
authors.initials: OC
authors.lastname: Jeon
authors.forename: Dong Yun
authors.initials: DY
authors.lastname: Lee
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D018938:Caco-2 Cells; D002756:Cholagogues and Choleretics / Q000494:pharmacology / Q000627:therapeutic use; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy*; D004285:Dogs; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D010180:Pancreatectomy
chemical_list: D001786:Blood Glucose; D002756:Cholagogues and Choleretics; D007004:Hypoglycemic Agents; D007328:Insulin; D003840:Deoxycholic Acid