Drug Transport and Metabolism in Rat and Human Intestine

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: One of the aims of this thesis was to investigate the involvement of efflux proteins, such as the P-glycoprotein (Pgp), in the drug transport in different regions of the rat and the human intestine. The intestinal extrusion of intracellularly formed CYP3A4 metabolites, including whether this extrusion might be mediated by Pgp, was also studied. The model drugs used were local anaesthetics (LA), which have been evaluated for inflammatory bowel disease, such as ropivacaine, lidocaine and bupivacaine. The intestinal permeability to LAs was found to be high throughout all intestinal regions of the rat and human intestine. Results from the Ussing chamber model indicated only minor efflux involvement as the drug permeability was higher in the serosa to mucosa transport direction than in the opposite direction. However, the involvement of efflux in the absorption of LAs could not be verified using in situ single-pass perfusion of rat jejunum. The extrusion of the ropivacaine metabolite, 2´,6´-pipecoloxylidide (PPX), was polarized to the mucosal reservoir of the Ussing chamber for both rat and human intestinal samples, and was probably not caused by any Pgp involvement. The expression levels of CYP3A4 and efflux transporters were consistent with the enzymes’ activity in human intestine. PPX formation was mediated by CYP3A4 in human intestine, and cyp2c and cyp2d in rat intestine. Species differences were observed, as PPX was formed in rat colon, but not human colon. In conclusion, the permeability of ropivacaine, lidocaine and bupivacaine was not subjected to efflux transport of significance for their intestinal uptake. The transport of ropivacaine metabolites to the mucosal compartment was probably not mediated by Pgp. The Ussing chamber model showed consistent results with those from intestinal microsomes as far as intestinal metabolism is concerned, making it a suitable model for investigations of the interplay of efflux and metabolism.