Pharmaceutical Research

, Volume 22, Issue 5, pp 721–727 | Cite as

Experimental and Computational Studies of Epithelial Transport of Mefenamic Acid Ester Prodrugs

  • Kamonthip Wiwattanawongsa
  • Vimon TantishaiyakulEmail author
  • Luelak Lomlim
  • Yon Rojanasakul
  • Sirirat Pinsuwan
  • Sanae Keawnopparat
Research Paper



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 modulators


Bidirectional transport studies were performed using Caco-2 cells. Compounds exhibiting an efflux ratio of ≥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.

Key Words:

Caco-2 MRP P-gp prodrugs transport 


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Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Kamonthip Wiwattanawongsa
    • 1
  • Vimon Tantishaiyakul
    • 1
    Email author
  • Luelak Lomlim
    • 1
  • Yon Rojanasakul
    • 2
  • Sirirat Pinsuwan
    • 3
  • Sanae Keawnopparat
    • 3
  1. 1.Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical SciencesPrince of Songkla UniversityHat-Yai, SongkhlaThailand
  2. 2.Department of Basic Pharmaceutical Sciences, School of PharmacyWest Virginia UniversityMorgantownUSA
  3. 3.Department of Pharmaceutical Technology, Faculty of Pharmaceutical SciencesPrince of Songkla UniversityHat-Yai, SongkhlaThailand

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