Prediction of Oral Absorption of Anionic Drugs that are Absorbed by the Monocarboxylic Acid Transport System

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Transcellular transport of carbenicillin (CBPC) and caridacillin (CIPC) through Caco-2 cell monolayer in the apical to basal direction was measured. CBPC is used pareterally because of poor absorption from the intestine, whereas CIPC is a prodrug of CBPC and is orally administered. Caco-2 cells were cultured on Transwell and the transport was measured at apical pH=6.0 and basal pH=7.4. Permeability of CIPC through Caco-2 cell monolayer was ca. 40-fold greater than that of CBPC, indicating that improved absorption of CIPC is due to much faster transport through the intestinal epithelial cells. Moreover, it was shown that CIPC, not CBPC, was transported by the monocarboxylic acid transport system that is located at the epithelial cells. It is probably true that modification of chemical structure from CBPC to CIPC resulted in much greater affinity to the transport system, which in turn resulted in greater absorption of the prodrug.Transport of cloxacillin (MCIPC), dicloxacillin (MDIPC), phenethicillin (PEPC), phenoxymethylpenicillin (PCV) and propicillin (PPPC) through Caco-2 cell monolayer was measured. Permeability of these drugs ranged from 0.8 to 1.0 x 10^<-6> cm/s. If we assume that these drugs are absorbed only by passive diffusion, extent of absorption after oral administration should be 10-20% of the dose (S.Chong et al., Pharm.Res.13 : 120-123, 1996). However, extent of oral absorption of these drugs in humans is 45-86%, which is much greater than that predicted assuming passive diffusion. The results suggest that a transport system, most probably the monocarboxylic acid transport system, is involved in the absorption of these drugs since these drugs have a carboxylic acid moiety and exist as mono-anion at physiological pH.Moreover, in our previous study, it was demonstrated that these drugs have affinity to the monocarboxylic acid transport system.