Characterization of mefenamic acid-guaiacol ester: stability and transport across Caco-2 cell monolayers.
OBJECTIVE
Prodrug of non-steroidal anti-inflammatory drugs (NSAIDs) or NSAIDs linked with guaiacol have been reported to suppress gastrointestinal (GI) toxicity or induce GI protective effect. In this study. mefenamic-guaiacol ester was synthesized and its physicochemical properties. stability, and transport across Caco-2 monolayers were investigated.


METHODS
Synthesis of the ester was carried out using mefenamic acid, guaiacol. N. N'-dimethylaminopyridine, and N,N'dicyclohexylcarbodiimide. The hydrolysis of the ester was investigated in aqueous buffer solutions pH 1-12 as well as in Caco-2 homogenate, human plasma, and porcine liver esterase. Caco-2 cell monolayers were utilized for transport studies. Due to the high lipophilicity of the ester with a calculated logP of 6.15, bovine serum albumin (BSA, 4%) was included in the receiver compartment to obtain a good in vitro-in vivo correlation. Permeation of the ester was assessed with or without the exposure of cells to PMSF, an inhibitor of esterase.


RESULTS
The ester was stable at a wide pH range from 1-10. However, it was hydrolyzed by enzymes from porcine liver esterase and Caco-2 homogenate. With the PMSF exposure on the apical (AP) side and in the presence of 4% BSA on the basolateral (BL) side, the transported amount of the ester from AP-to-BL direction was 14.63% after 3 hr with a lag time of 23 min. The Papp for the ester was 4.72 x 10(-6) cm s(-1).


CONCLUSIONS
The results from hydrolysis studies indicate that this ester is a prodrug. The Papp value suggests the moderate absorption characteristic of the compound. The accumulation of this highly lipophilic ester in Caco-2 cells is reduced in the presence of BSA.
Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Thailand. tvimon@ratree.psu.ac.th
Vimon
V
Tantishaiyakul
Kamonthip
K
Wiwattanawongsa
Sirirat
S
Pinsuwan
Srirat
S
Kasiwong
Narubodee
N
Phadoongsombut
Sanae
S
Kaewnopparat
Nattha
N
Kaewnopparat
Yon
Y
Rojanasakul
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D018938:Caco-2 Cells / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004355:Drug Stability; D006139:Guaiacol / Q000031:analogs & derivatives; D006801:Humans; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D008528:Mefenamic Acid / Q000737:chemistry / Q000493:pharmacokinetics*; D013552:Swine
C020176:metoxibutropate; D008528:Mefenamic Acid; D006139:Guaiacol; D007052:Ibuprofen