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Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery.
- Source :
-
Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 1999 Nov 01; Vol. 62 (1-2), pp. 25-31. - Publication Year :
- 1999
-
Abstract
- Cytochrome P-450 3A4 (CYP3A4), the major phase I drug metabolizing enzyme in humans, and the multidrug efflux pump, MDR or P-glycoprotein (P-gp), are present at high levels in the villus tip enterocytes of the small intestine, the primary site of absorption for orally administered drugs. These proteins are induced or inhibited by many of the same compounds and demonstrate a broad overlap in substrate and inhibitor specificities, suggesting that they act as a concerted barrier to drug absorption. A series of studies from our laboratory of cyclosporine and tacrolimus in humans and a novel cysteine protease inhibitor in rats, dosed concomitantly with inhibitors and inducers of CYP3A4 and P-gp, suggest that gut extraction can be modeled using measures of intestinal metabolism and absorption rate, the latter reflecting changes in P-gp. Results evaluating a preliminary model applied to the CYP3A substrate drugs midazolam, indinavir, saquinavir, and rifabutin suggest that the model may be useful for predicting in vivo intestinal metabolism from in vitro data.
- Subjects :
- Administration, Oral
Animals
Biological Availability
Biological Transport
Cell Line
Cysteine Proteinase Inhibitors pharmacology
Liver metabolism
Models, Biological
Rats
Transfection
ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Carrier Proteins metabolism
Cytochrome P-450 Enzyme System metabolism
Drug Delivery Systems
Intestinal Absorption
Subjects
Details
- Language :
- English
- ISSN :
- 0168-3659
- Volume :
- 62
- Issue :
- 1-2
- Database :
- MEDLINE
- Journal :
- Journal of controlled release : official journal of the Controlled Release Society
- Publication Type :
- Academic Journal
- Accession number :
- 10518631
- Full Text :
- https://doi.org/10.1016/s0168-3659(99)00034-6