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Enantioselective transport and CYP3A4-mediated metabolism of R/S-verapamil in Caco-2 cell monolayers
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
2003 In: European Journal of Pharmaceutical Sciences, Vol. 19, 57-65 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2003. Vol. 19, 57-65 p.
URN: urn:nbn:se:uu:diva-90889OAI: oai:DiVA.org:uu-90889DiVA: diva2:163398
Available from: 2003-09-24 Created: 2003-09-24Bibliographically approved
In thesis
1. Intestinal barriers to oral drug absorption: Cytochrome P450 3A and ABC-transport proteins
Open this publication in new window or tab >>Intestinal barriers to oral drug absorption: Cytochrome P450 3A and ABC-transport proteins
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The subject of this thesis was to study two intestinal barriers to oral drug bioavailability, drug efflux proteins of the ABC-transporter family, and in particular ABCB1/P-glycoprotein (Pgp), and the drug metabolizing enzyme cytochrome P450 (CYP) 3A4. At the onset of this thesis, similarities between CYP3A4 and Pgp in terms of their tissue distribution and gene regulation, along with overlapping substrate specificities, had generated the hypothesis that CYP3A4 and Pgp may have a complementary function and thus form a coordinated intestinal barrier to drug absorption and gut wall metabolism.

In the first part of this thesis, a cell culture model of the intestinal epithelium that expressed both functional Pgp and CYP3A4 was developed. This model was then used to investigate the steroselective drug efflux and metabolism of R/S-verapamil. In summary, the results indicated that the two barriers in the cell culture model were in agreement with those in the human intestine.

Both ABC-transporters and CYPs are regulated by drugs that interact with nuclear receptors. However, while the regulation of CYPs is quite well understood, less is known about how repeated drug administration regulates the most abundantly expressed ABC-transporters. Therefore, in the second part of this thesis, the effects of repeated drug administration on the gene regulation of four ABC-transporters and CYP3A4 were studied in intestinal epithelial cell lines in vitro and in the perfused human jejunum in vivo. The in vitro studies revealed that the ABC-transporters are induced by drugs that interact with slightly different sets of nuclear receptors. The in vivo study showed that repeated oral administration of St John’s wort decreased the bioavailability of verapamil, predominantly by induction of intestinal CYP3A4. This part of the thesis provides new information about the regulation of ABC-transporters, shows that the intestinal metabolism is the most significant barrier to oral bioavailability of verapamil and provides evidence for a clinically significant interaction between verapamil and St John’s wort in vivo.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 61 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 296
Pharmaceutics, oral drug delivery, bioavailability, human jejunum, Caco-2, ABC-transporter, P-glycoprotein, CYP3A, Galenisk farmaci
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-3599 (URN)91-554-5752-5 (ISBN)
Public defence
2003-10-17, B21, Uppsala Biomedical Centre, Uppsala, 10:15
Available from: 2003-09-24 Created: 2003-09-24Bibliographically approved

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