Investigation of the Effect of the Uneven Distribution of CYP3A4 and P-Glycoprotein in the Intestine on the Barrier Function against Xenobiotics: A Simulation Study
| Autor: | Takao Watanabe, Kazuya Maeda, Yuichi Sugiyama, Chikako Nakai |
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| Rok vydání: | 2013 |
| Předmět: |
Biological Availability
Pharmaceutical Science Models Biological Permeability Intestinal absorption Xenobiotics chemistry.chemical_compound medicine Cytochrome P-450 CYP3A Humans Distribution (pharmacology) Computer Simulation ATP Binding Cassette Transporter Subfamily B Member 1 Intestinal Mucosa Barrier function P-glycoprotein biology Permeation Small intestine medicine.anatomical_structure Membrane Intestinal Absorption Biochemistry chemistry biology.protein Biophysics Xenobiotic |
| Zdroj: | Journal of Pharmaceutical Sciences. 102:3196-3204 |
| ISSN: | 0022-3549 |
| DOI: | 10.1002/jps.23623 |
| Popis: | CYP3A4 and P-glycoprotein (P-gp) have similar substrate specificities and work together to form an intestinal absorption barrier against xenobiotics. Previous reports have indicated that CYP3A4 expression decreases gradually, whereas P-gp expression increases, from the upper to lower small intestine. The physiological rationale for this uneven distribution of CYP3A4 and P-gp as a barrier against xenobiotics has not been determined. To clarify the effect of these distribution patterns on barrier function, we constructed a mathematical model that included passive membrane permeation, P-gp-mediated apical efflux, and CYP3A4-mediated metabolism, and we simulated the effects of these distribution patterns on the fraction absorbed of co-substrates without changing their overall activities. The simulation showed that the physiological distribution patterns of both CYP3A4 and P-gp result in the lowest fraction absorbed, but not for drugs with low CYP3A4 and high P-gp-mediated clearances. These results suggest that the distribution pattern of CYP3A4 is especially important for the barrier function. On the other hand, physiological distribution pattern of P-gp exerts the maximum barrier function for dual good substrates for P-gp and CYP3A4, but even distribution of P-gp mostly suppresses the intestinal absorption of good P-gp, but poor CYP3A4 substrates. |
| Databáze: | OpenAIRE |
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