Experimental and Computational Studies of Epithelial Transport of Mefenamic Acid Ester Prodrugs
| Autor: | Sirirat Pinsuwan, Kamonthip Wiwattanawongsa, Vimon Tantishaiyakul, Luelak Lomlim, Sanae Keawnopparat, Yon Rojanasakul |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Mefenamic acid Gastrointestinal toxicity Pharmaceutical Science Biopharmaceutics Rats Sprague-Dawley Mefenamic Acid Enzyme Stability medicine Animals Humans Technology Pharmaceutical Organic chemistry Computer Simulation Prodrugs Pharmacology (medical) Pharmacology chemistry.chemical_classification Ester derivatives Chemistry Organic Chemistry Epithelial Cells Transporter Prodrug Fluoresceins Rats Enzyme Solubility Caco-2 Epithelial transport Molecular Medicine Caco-2 Cells Biotechnology medicine.drug |
| Zdroj: | Pharmaceutical Research. 22:721-727 |
| ISSN: | 1573-904X 0724-8741 |
| Popis: | A series of ester derivatives of mefenamic acid were synthesized with the aim of suppressing local gastrointestinal toxicity of mefenamic acid. A computational method was used to assist the design of the prodrug and to gain insights into the structure relationship of these compounds as P-glycoprotein (P-gp) substrates. The prodrugs were studied for their enzymatic stability, bidirectional permeability across Caco-2 monolayer, and their potential as transporter modulatorsBidirectional transport studies were performed using Caco-2 cells. Compounds exhibiting an efflux ratio ofor =2 were further examined for their potential interaction with P-gp and multidrug resistance-associated protein (MRP) using verapamil and indomethacin. Calcein efflux inhibition studies were conducted to investigate the efflux mechanism of these compounds. Geometry optimization of the esters was performed, and the spatial separation of two electron donor groups of each prodrug was measured.Morpholinoethyl ester (3) and pyrrolidinoethyl ester (4) of mefenamic acid showed evidence of efflux mechanism. Inhibition by verapamil had a pronounced effect on the transport of 3 and 4. Indomethacin, however, completely inhibited the apical efflux of 3 but enhanced the efflux ratio of 4. Both compounds increased the ratio of cellular calcein accumulation by 3- to 5-fold over control. Consistent with the experimental data, the computational results suggest the involvement of P-gp or its interaction in 3 and 4 transport.Apical efflux of 3 is associated with P-gp and MRP, but the efflux of 4 involves P-gp and/or MRP. The computational approach used in this study provided the basis for P-gp substrates of compounds 3 and 4 from their electron donor subunits spatial separation. |
| Databáze: | OpenAIRE |
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