NDLI: Characterization of the Efflux Transporter(s) Responsible for Restricting Intestinal Mucosa Permeation of an Acyloxyalkoxy-Based Cyclic Prodrug of the Opioid Peptide DADLE

Content Provider	Springer Nature Link
Author	Tang, Fuxing Borchardt, Ronald T.
Copyright Year	2002
Abstract	Purpose. To elucidate the efflux transporter(s) responsible for restricting the permeation of an acyloxyalkoxy-based cyclic prodrug of the opioid peptide DADLE (AD) through Caco-2 cell monolayers. Methods. The cellular permeation characteristics of AD were investigated using Caco-2 cells, Madin-Darby canine kidney wild-type II cells (MDCK-WT), MDCK cells transfected with the human MDR1 gene (MDCK-MDR1), and MDCK cells transfected with the human MRP2 gene (MDCK-MRP2). These cells were grown as monolayers onto microporous membranes. The disappearance of AD from the donor side and its appearance on the receiver side were monitored by high-performance liquid chromatography. The substrate activity of AD for P-glycoprotein (P-gp) was determined using GF120918, a known P-gp specific inhibitor. The substrate activity of AD for MRP2 was determined by using cyclosporin A, a known MRP2 and P-gp inhibitor. Results. In Caco-2 cells, the ratio of the apparent permeability coefficients (P$_{app}$) of AD flux measured in the basolateral (BL) to apical (AP) direction vs. the flux in the AP-to-BL direction (P$_{app BL-to-AP}$/P$_{app AP-to-BL}$) was 99. In the presence of 2 μM GF120918 or 25 μM cyclosporin A, the P$_{app BL-to-AP}$/P$_{app AP-to-BL}$ ratio was decreased to 11. In MDCK-WT, MDCK-MDR1, and MDCK-MRP2 cells, the P$_{app BL-to-AP}$/P$_{app AP-to-BL}$ ratios of AD were 4.7, 10, and 5.8, respectively. A mixture of GF120918 (2 μM) and cyclosporin A (25 μM) decreased the P$_{app BL-to-AP}$/P$_{app AP-to-BL}$ ratios of AD in MDCK-WT, MDCK-MDR1, and MDCK-MRP2 cells to 1.2, 1.8, and 2.3, respectively. Conclusions. These data suggest that AD is a much better substrate for P-gp than MRP2 and that the restricted permeation of this cyclic prodrug in Caco-2 cells and in the intestinal mucosa probably is due primarily to its substrate activity for P-gp.
Starting Page	780
Ending Page	786
Page Count	7
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	19
Issue Number	6
e-ISSN	1573904X
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2002-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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