title: Biochemical, pharmaceutical and therapeutic properties of long-acting lithocholic acid derivatized exendin-4 analogs.
abstract: Alterations in the physicochemical characteristics of peptide drugs can transform their biological and pharmaceutical features. In the present study, we explored the potentials of lithocholic acid (LCA)-modified exendin-4 derivatives as novel long-acting GLP-1 receptor agonists. Exendin-4 was modified with lithocholic acid at two lysine residues to produce three derivatives that were obtained by reverse-phase HPLC separation, namely, Lys(12)-LCA-exendin-4 (LCA-M2), Lys(27)-LCA-exendin-4 (LCA-M1), and Lys(12,27)-LCA-exendin-4 (LCA-Di)). The biological, pharmacological, and physicochemical characteristics of these three exendin-4 analogues were then investigated. Although slight reductions in the GLP-1 receptor binding capacity and insulinotropic activity of exendin-4 were observed after derivatization, the mono-LCA substitutions, especially LCA-M1, well-preserved antidiabetic activity in type 2 diabetic mice when administered subcutaneously or intraperitoneally. Furthermore, the pharmacokinetic characteristics were dramatically enhanced, that is, absorption was delayed and elimination half-life was increased (1.6+/-0.4 and 9.7+/-1.4h by exendin-4 and LCA-M1, respectively). The enhanced long-acting characteristics of the derivative was found to be due to albumin binding and nanoparticle formation, and these were verified by the restoration of normoglycemia in type 2 diabetic mice after single injection (>24h, >10 nmol/kg, s.c.) and daily injections (15 nmol/kg/day) maintained normoglycemia for the 4-week administration period. Furthermore, antidiabetic potentials, such as, glucose clearance kinetics and percentage areas occupied by pancreatic beta-cells were also enhanced by long-term LCA-M1 administration. The present study demonstrates that the derivatization of exendin-4 with LCA offers a possible means of producing a long-acting GLP-1 receptor agonist.
authors.affiliation: College of Pharmacy, SungKyunKwan University, 300 Chonchon-dong, Jangan-ku, Suwon City 440-746, South Korea.
authors.forename: Su Young
authors.initials: SY
authors.lastname: Chae
authors.forename: Cheng-Hao
authors.initials: CH
authors.lastname: Jin
authors.forename: Jae Hee
authors.initials: JH
authors.lastname: Shin
authors.forename: Sohee
authors.initials: S
authors.lastname: Son
authors.forename: Tae Hyung
authors.initials: TH
authors.lastname: Kim
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Youn
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008095:Lithocholic Acid / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014688:Venoms / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D008095:Lithocholic Acid; D000077270:Exenatide