کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2484834 | 1114338 | 2013 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: 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 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](/preview/png/2484834.png)
ABSTRACTCYP3A4 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.
Journal: Journal of Pharmaceutical Sciences - Volume 102, Issue 9, September 2013, Pages 3196–3204