☆ 4.8 Article

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

JOURNAL OF CONTROLLED RELEASE (2010)

Journal

JOURNAL OF CONTROLLED RELEASE

Volume 142, Issue 2, Pages 206-213

Publisher

ELSEVIER SCIENCE BV

DOI: 10.1016/j.jconrel.2009.10.025

Keywords

GLP-1 receptor agonists; Exendin-4; Lithocholic acid; Bioconjugation; Type 2 diabetic mellitus

Funding

Korean Government (MOEHRD) [KRF-2006-353-E00022]
Ministry of Education, Science and Technology in Korea [2009-0081871]
National Research Foundation of Korea [2009-0081871, 2010-50196, 과C6A2103] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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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 +/- 1.4 h 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 (> 24 h, > 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 P-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. (C) 2009 Elsevier B.V. All rights reserved.

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Gut Microbial Signatures for Glycemic Responses of GLP-1 Receptor Agonists in Type 2 Diabetic Patients: A Pilot Study

Chih-Yiu Tsai, Hsiu-Chen Lu, Yu-Hsien Chou, Po-Yu Liu, Hsin-Yun Chen, Meng-Chuan Huang, Chia-Hung Lin, Chi-Neu Tsai

Summary: This pilot study aimed to identify microbial signatures associated with glycemic responses to GLP-1 RA treatment in patients with T2D. The results showed that the microbial diversity differed significantly between responders and non-responders, and specific microbial features were correlated with glycemic reduction. These findings indicate that gut microbiota may play a role in the heterogeneity of responses to GLP-1 RA treatment in T2D.

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