Biochemical, pharmaceutical and therapeutic properties of long-acting lithocholic acid derivatized exendin-4 analogs

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 modifi...

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Veröffentlicht in:Journal of controlled release 2010-03, Vol.142 (2), p.206-213
Hauptverfasser: SU YOUNG CHAE, JIN, Cheng-Hao, JAE HEE SHIN, SON, Sohee, TAE HYUNG KIM, LEE, Seulki, YU SEOK YOUN, BYUN, Youngro, LEE, Myung-Shik, KANG CHOON LEE
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Sprache:eng
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Zusammenfassung: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.
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2009.10.025