A comparison of the effects of p-glycoprotein inhibitors on the blood-brain barrier permeation of cyclic prodrugs of an opioid peptide (DADLE).
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 P-gp 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 = CyA >or= PSC-833; and by in situ rat brain perfusion: GF-120918 > CyA = 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.
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047, USA. ouyang_fred@allergan.com
Hui
H
Ouyang
Thomas E
TE
Andersen
Weiqing
W
Chen
Rebecca
R
Nofsinger
Bente
B
Steffansen
Ronald T
RT
Borchardt
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D008954:Models, Biological; D018847:Opioid Peptides / Q000737:chemistry / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism; D010477:Perfusion; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*; D011802:Quinidine / Q000378:metabolism; D051381:Rats
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018847:Opioid Peptides; D010456:Peptides, Cyclic; D011355:Prodrugs; D011802:Quinidine