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


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.


CONCLUSIONS
The results indicate that exendin-4 is well conformed for exerting central effects involved in the control of obesity.
Kastin
A J
AJ
VA Medical Center and Tulane University School of Medicine, New Orleans, LA 70112-1262, USA.
Akerstrom
V
V
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004353:Drug Evaluation, Preclinical; D000077270:Exenatide; D006860:Hydrogen Bonding; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D000442:Octanols; D010455:Peptides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D014688:Venoms
D000442:Octanols; D010455:Peptides; D014688:Venoms; D000077270:Exenatide