A comparison of the effects of p-glycoprotein inhibitors on the blood–brain barrier permeation of cyclic prodrugs of an opioid peptide (DADLE)

✍ Scribed by Hui Ouyang; Thomas E. Andersen; Weiqing Chen; Rebecca Nofsinger; Bente Steffansen; Ronald T. Borchardt

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 156 KB
• Volume: 98
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.21585

✦ Synopsis

The objective of this study was to elucidate the role of P-glycoprotein (P-gp) in restricting the blood-brain barrier (BBB) permeation of cyclic prodrugs of the opioid peptide DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH). The BBB permeation characteristics of these prodrugs and DADLE were determined using an in situ perfused rat brain model and in vitro cell culture model (MDCK-MDR1 cells) of the BBB. The activities of Pgp in these models were characterized using a known substrate (quinidine) and known inhibitors [cyclosporine A (CyA), GF-120918, PSC-833] of P-gp. Cyclic peptide prodrugs exhibited very poor permeation in both models. Inclusion of GF-120918, CyA, or PSC-833 in the brain perfusion medium or the cell culture medium significantly increased the permeation of these cyclic prodrugs. The order of potency of these P-gp inhibitors, as measured using the cyclic prodrugs as substrates, was, by in vitro MDCK-MDR1 cells: GF-120918 ¼ CyA ! PSC-833; and by in situ rat brain perfusion: GF-120918 > CyA ¼ PSC-833. In conclusion, P-gp in the BBB is the major factor restricting the brain permeation of these cyclic prodrugs. MDCK-MDR1 cells can predict the order of potencies of the investigated P-gp inhibitors to enhance the rat BBB permeation of quinidine and the cyclic prodrugs.