ArticlePharmaceutical research2002
Characterization of the efflux transporter(s) responsible for restricting intestinal mucosa permeation of the coumarinic acid-based cyclic prodrug of the opioid peptide DADLE.
Article in Pharmaceutical research, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 37 citations in OpenAlex.
- Cyclic Opioid Peptides.Current medicinal chemistry · 2016Review
- Strategic approaches to optimizing peptide ADME properties.The AAPS journal · 2015Review
- Development of a sensitive HPLC method to measure in vitro permeability of E- and Z-isomeric forms of thiosemicarbazones in Caco-2 monolayers.Journal of chromatography. B, Analytical technologies in the biomedical and life sciences · 2012Article
- Targeted lipid based drug conjugates: a novel strategy for drug delivery.International journal of pharmaceutics · 2012Article
- Cyclization-activated prodrugs.Molecules (Basel, Switzerland) · 2007Review
- Transport characteristics of fexofenadine in the Caco-2 cell model.Pharmaceutical research · 2004Article
- Efflux ratio cannot assess P-glycoprotein-mediated attenuation of absorptive transport: asymmetric effect of P-glycoprotein on absorptive and secretory transport across Caco-2 cell monolayers.Pharmaceutical research · 2003Article
- Are MDCK cells transfected with the human MDR1 gene a good model of the human intestinal mucosa?Pharmaceutical research · 2002Article
- A modified coumarinic acid-based cyclic prodrug of an opioid peptide: its enzymatic and chemical stability and cell permeation characteristics.Pharmaceutical research · 2002Article
- Functional characterization of sodium-dependent multivitamin transporter in MDCK-MDR1 cells and its utilization as a target for drug delivery.Molecular pharmaceuticsArticle
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2 authors at 1 institution in 1 country.
Funding
Abstract
purposeTo elucidate the efflux transporter(s) responsible for restricting the permeation of a coumarinic acid-based cyclic prodrug of the opioid peptide DADLE (CD) thorough Caco-2 cell monolayers.
methodsThe cellular permeability characteristics of CD 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 human MRP2 gene (MDCK-MRP2). These cells were grown as monolayers onto microporous membranes. The disappearance from the donor side and appearance on the receiver side of CD were monitored by HPLC. The substrate activity of CD for P-gp was determined by using GF120918. a known P-gp specific inhibitor. The substrate activity of CD for MRP2 was determined by using cyclosporin A (CsA), a known MRP2 and P-gp inhibitor.
resultsIn Caco-2 cells, the ratio of the apparent permeability coefficients (Papp) of CD flux in the basolateral (BL) to apical (AP) direction vs. the flux in the AP-to-BL direction (Papp-BL-to-AP/Papp AP-to-BL) was 71. In the presence of GF120918 (2 microM), the Papp BL-to-AP/Papp AP-to-BL ratio was decreased to 16. In the presence of CsA (25 microM), the ratio was decreased to 5.6. In MDCK-WT. MDCK-MDR1, and MDCK-MRP2 cells, the Papp BL-AP/Papp AP-to-BL ratios of CD were 13, 35, and 22, respectively. CsA (25 microM) greatly decreased the Papp BL-P-AP/Papp AP-to-BL ratios in MDCK-WT and MDCK-MDR1 cells to 1.5 and 3.2, respectively. However, in MDCK-MRP2 cells. CsA (25 microM) decreased the ratio only to 11. A mixture of GF120918 (2 microM) and CsA (25 microM) decreased the Papp BL-to-AP/Papp AP-to-BL ratios of CD in MDCK-WT, MDCK-MDR1, and MDCK-MRP2 cells to 1.4, 2.7, and 5.4. respectively.
conclusionsThese data suggest that CD is a good substrate for both P-gp and MRP2 and that the restricted permeation of this cyclic prodrug in Caco-2 cells and in the intestinal mucosa is probably due to its substrate activities for both of these efflux transporters.
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