Preparation and evaluation of palmitic acid-conjugated exendin-4 with delayed absorption and prolonged circulation for longer hypoglycemia
- Authors
- Lee, Juho; Lee, Changkyu; Kim, Insoo; Moon, Hyung Ryong; Kim, Tae Hyung; Oh, Kyung Taek; Lee, Eun Seong; Lee, Kang Choon; Youn, Yu Seok
- Issue Date
- Mar-2012
- Publisher
- ELSEVIER SCIENCE BV
- Keywords
- Exendin-4; Palmitic acid; Albumin-binding; Type 2 diabetes; Hypoglycemia
- Citation
- INTERNATIONAL JOURNAL OF PHARMACEUTICS, v.424, no.1-2, pp 50 - 57
- Pages
- 8
- Journal Title
- INTERNATIONAL JOURNAL OF PHARMACEUTICS
- Volume
- 424
- Number
- 1-2
- Start Page
- 50
- End Page
- 57
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/20441
- DOI
- 10.1016/j.ijpharm.2011.12.050
- ISSN
- 0378-5173
1873-3476
- Abstract
- Albumin-binding achieved by fatty-acylation to drugs is considered to be an effective means of prolonging the circulation lifetimes of short-lived peptides. Here, exendin-4 was modified with palmitic acid, and the particle size and albumin-binding of palmitic acid-conjugated exendin-4 (Pal-Ex4) purified was investigated and visualized. Additionally, its pharmacokinetics and pharmacodynamics were evaluated in diabetic rodents. Pal-Ex4 had a greater molecular size (similar to 125 nm) and its albumin-binding was 5.6-fold that of Ex4. Molecular imaging showed that the subcutaneous absorption of Pal-Ex4 was delayed until 24 h post-injection, whereas Ex4 was rapidly absorbed and distributed systemically. Pharmacokinetic and pharmacodynamic results confirmed these observations, for example, times to reach peak concentration and to achieve a blood glucose level nadir were greatly delayed versus Ex4, and the circulating half-life of Pal-Ex4 was much greater than that of Ex4. Consequently, the hypoglycemic degree of Pal-Ex4 (500 nmol/kg) was 4.2 fold greater than Ex4. Our results show that the extended hypoglycemic efficacy of Pal-Ex4 was due to (i) a delayed absorption due to micelle formation and (ii) an increased in vivo circulating half-life due to albumin-binding. We believe that this prototype of exendin-4 has considerable pharmaceutical potential as a systemic type 2 anti-diabetic treatment. (C) 2012 Elsevier B.V. All rights reserved.
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