The Role of P-Glycoprotein in Intestinal Transport versus the BBB Transport of Tetraphenylphosphonium
| Autor: | Amnon Hoffman, Hila Zohar-Kontante, Lola Weiss, Igal Madar, Sara Eyal, Avi Swed |
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| Rok vydání: | 2009 |
| Předmět: |
Pharmaceutical Science
Cyclosporins In Vitro Techniques Pharmacology Mice Onium Compounds Organophosphorus Compounds In vivo Cyclosporin a Drug Discovery ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 Enzyme Inhibitors Intestinal Mucosa P-glycoprotein Mice Knockout biology Uncoupling Agents Chemistry Multidrug resistance-associated protein 2 Biological Transport Calcium Channel Blockers Multidrug Resistance-Associated Protein 2 In vitro Rats Verapamil Blood-Brain Barrier Knockout mouse Cyclosporine Quinolines biology.protein Leukotriene Antagonists Molecular Medicine ATP-Binding Cassette Transporters Female Efflux Caco-2 Cells Multidrug Resistance-Associated Proteins Propionates 2 4-Dinitrophenol Ex vivo |
| Zdroj: | Molecular Pharmaceutics. 6:1883-1890 |
| ISSN: | 1543-8392 1543-8384 |
| Popis: | Tetraphenylphosphonium (TPP), a phosphonium cation, is a promising means for tumor imaging. A major contributor to the pharmacokinetics of phosphonium cations is the efflux transporter P-glycoprotein (P-gp). For this application it is important to ascertain the influence of the multidrug resistance system on TPP. Therefore, our aim was to characterize the interaction of TPP with P-gp, in vitro and in in vivo models. P-gp-mediated transport of [3H]-TPP was assessed in Caco-2 cells and ex vivo in rat intestinal wall by the use of a diffusion cell system. The distribution of [3H]-TPP across the blood-brain barrier (BBB) was studied in rats and mice treated with P-gp modulators and in Mdr-1a/b((-/-)) knockout mice. The in vitro permeability coefficient of basolateral-to-apical transfer (PappB-A) of [3H]-TPP was 8-fold greater than apical-to-basolateral (PappA-B) coefficient, indicative of net mucosal secretion. A concentration dependent decrease of this secretion was obtained by the P-gp substrate verapamil, while no effect was evident by the MRP2 inhibitor MK-571 and the BCRP inhibitor FTC. [3H]-TPP transfer across rat jejunum wall was directional and concentration-dependent. 2,4-Dinitrophenol, cyclosporin A (CsA), verapamil and PSC-833 enhanced A-B transport of TPP 3.6-fold, 4-fold, 4.6-fold and 5.3-fold respectively. Likewise, PappA-B of [3H]-TPP was 5-fold greater in P-gp knockout mice than in controls. In vivo, PSC-833, P-gp inhibitor, significantly increased the uptake of [3H]-TPP in the liver, heart, small intestine and the lungs but not the brain. Similar results were obtained in P-gp knockout mice. Our study demonstrates that P-gp mediates TPP efflux in vitro and in vivo; however, the consistently poor BBB permeation of TPP in all in vivo studies including P-gp knockout animals indicates that it is most likely mediated by other mechanisms. These findings are important for optimized clinical application of TPP as an imaging agent in cancer. |
| Databáze: | OpenAIRE |
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