Entry of exendin-4 into brain is rapid but may be limited at high doses

Int J Obes Relat Metab Disord. 2003 Mar;27(3):313-8. doi: 10.1038/sj.ijo.0802206.


Objective: Peripherally administered exendin-4 is in clinical trials for the treatment of diabetes mellitus and obesity. Since its effects on food intake are mediated centrally, we determined the degree and type of its blood-to-brain penetration of the mouse blood-brain barrier (BBB).

Measurements and results: High-performance liquid chromatography showed that exendin-4 was stable in blood, with most of the injected peptide reaching the brain intact. Capillary depletion studies with washout showed that the injected exendin-4 reached brain parenchyma rather than being trapped in the endothelial cells composing the BBB. Multiple-time regression analysis showed that exendin-4 crossed the BBB directly at a fast rate. The rapid brain entry of exendin-4, helped by its high lipophilicity as demonstrated by the octanol/buffer partition coefficient, was not dependent upon circumventricular organs and was not affected by food deprivation for 24 h. The simultaneous i.v. injection of high doses of unlabeled exendin-4 resulted in self-inhibition (saturation) that only became statistically significant (P<0.05) when the results of four experiments were combined; this suggests a possible limit to the amount of peripherally administered exendin-4 that can reach the brain after injection of high doses.

Conclusion: The results indicate that exendin-4 is well conformed for exerting central effects involved in the control of obesity.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood-Brain Barrier
  • Brain / metabolism*
  • Chromatography, High Pressure Liquid / methods
  • Drug Evaluation, Preclinical
  • Exenatide
  • Hydrogen Bonding
  • Injections, Intravenous
  • Male
  • Mice
  • Mice, Inbred Strains
  • Octanols
  • Peptides / blood
  • Peptides / chemistry
  • Peptides / pharmacokinetics*
  • Venoms*


  • Octanols
  • Peptides
  • Venoms
  • Exenatide