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Gene and protein expression of P-glycoprotein, MRP1, MRP2 and CYP3A4 in the small and large human intestine
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2007 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, Vol. 4, no 2, 252-257 p.Article in journal (Refereed) Published
Abstract [en]

The cytochrome P450 3A4 enzyme and the ABC-transporters may affect the first-pass extraction and bioavailability of drugs and metabolites. Conflicting reports can be found in the literature on the expression levels of efflux transporters in human intestine and how they vary along the intestine. The relative levels of mRNA and protein of CYP3A4 and the ABC tranporters Pgp (ABCB1), MRP1 (ABCC1), and MRP2 (ABCC2) were determined using RT-PCR and Western blot for human intestinal tissues (n = 14) from jejunum, ileum and colon. The expression of mRNA for CYP3A4, Pgp, and MRP2 was highest in jejunum and decreased toward more distal regions, whereas MRP1 was equally distributed in all intestinal regions. For CYP3A4, a more significant correlation could be established between mRNA and protein expression than for the ABC transporters. The samples showed considerable interindividual variability, especially at the protein level. The apically located Pgp and MRP2 showed a similar expression pattern along the human intestine as for CYP3A4. The gene expression of MRP1 exhibited a more uniform distribution.

Place, publisher, year, edition, pages
2007. Vol. 4, no 2, 252-257 p.
Keyword [en]
P-glycoprotein, CYP3A4, MRP, human, intestine, RT-PCR, Western blot
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-95081DOI: 10.1021/mp0600687ISI: 000245316000008PubMedID: 17263554OAI: oai:DiVA.org:uu-95081DiVA: diva2:169155
Available from: 2006-11-10 Created: 2006-11-10 Last updated: 2011-02-02Bibliographically approved
In thesis
1. Drug Transport and Metabolism in Rat and Human Intestine
Open this publication in new window or tab >>Drug Transport and Metabolism in Rat and Human Intestine
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 53 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 41
Biopharmacy, Ussing chamber, microsome, single-pass perfusion, human, rat, intestine, permeability, efflux, P-glycoprotein, metabolism, cytochrome P450, ropivacaine, lidocaine, bupivacaine, Biofarmaci, PPX
urn:nbn:se:uu:diva-7229 (URN)91-554-6706-7 (ISBN)
Public defence
2006-12-01, B22, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2006-11-10 Created: 2006-11-10Bibliographically approved

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Lennernäs, Hans
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Department of PharmacyDepartment of Surgical Sciences
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