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Drug absorption across viable porcine intestines was investigated using an Ussing chamber system. The apparent permeability coefficients, P app,pig  , were compared to the permeability coefficients determined in humans in vivo, P eff,human  . Eleven drugs from the different Biopharmaceutical Classification System (BCS) categories absorbed by passive diffusion with published P eff,human  values were used to test the system. The initial experiments measured P app,pig  for each drug after application in a Krebs⁻Bicarbonate Ringer (KBR) buffer and in biorelevant media FaSSIF V2 and FeSSIF V2, mimicking fasted and fed states. Strong sigmoidal correlations were observed between P eff,human  and P app,pig  . Differences in the segmental P app,pig  of antipyrine, cimetidine and metoprolol confirmed the discrimination between drug uptake in the duodenum, jejunum and ileum (and colon); the results were in good agreement with human data in vivo. The presence of the P-gp inhibitor verapamil significantly increased P app,pig  across the ileum of the P-gp substrates cimetidine and ranitidine ( p &lt; 0.05). Clotrimazole, a potent CYP3A4 inhibitor, significantly increased P app,pig  of the CYP3A4 substrates midazolam, verapamil and tamoxifen and significantly decreased the formation of their main metabolites. In conclusion, the results showed that this is a robust technique to predict passive drug permeability under fasted and fed states, to identify regional differences in drug permeability and to demonstrate the activity of P-gp and CYP3A4.

pharmaceutics

Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption