Factors that restrict the intestinal cell permeation of cyclic prodrugs of an opioid peptide (DADLE): Part I. Role of efflux transporters in the intestinal mucosa.
The objective of this study was to elucidate the role of P-glycoprotein (P-gp) in restricting the intestinal mucosal permeation of cyclic prodrugs (AOA-DADLE, CA-DADLE, and OMCA-DADLE) of the opioid peptide DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH). In the Caco-2 cell model, the high P(app,BL-to-AP)/P(app,AP-to-BL) ratios of AOA-DADLE, CA-DADLE, and OMCA-DADLE (71-117) were significantly decreased by including known P-gp inhibitors, GF-12098, cyclosporine (CyA), or PSC-833, in the incubation media, suggesting that P-gp is restricting the AP-to-BL permeation of these cyclic prodrugs. In the in situ perfused rat ileum model, AOA-DADLE, CA-DADLE, and OMCA-DADLE were shown to exhibit very low permeation into the mesenteric blood (P(B) = 0.40, 0.56 and 0.42 x 10(-7) cm/s, respectively). PSC-833 was found to increase significantly the P(B) values for all three prodrugs. In contrast, CyA and GF-12918 were either inactive or substantially less active than PSC-833 in increasing the P(B) values of these prodrugs. These data suggest that, while P-gp plays a role, other factors (e.g., substrate activity for other efflux transporters and/or for metabolic enzymes) may contribute to restricting the permeation of AOA-DADLE, CA-DADLE, and OMCA-DADLE across the rat intestinal mucosa.
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047, USA.
Hui
H
Ouyang
Weiqing
W
Chen
Thomas E
TE
Andersen
Bente
B
Steffansen
Ronald T
RT
Borchardt
D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology*; D016308:Enkephalin, Leucine-2-Alanine / Q000493:pharmacokinetics*; D006801:Humans; D007082:Ileum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000502:physiology*; D018847:Opioid Peptides / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats
D026901:Membrane Transport Proteins; D018847:Opioid Peptides; D011355:Prodrugs; D016308:Enkephalin, Leucine-2-Alanine