Transport proteins and intestinal metabolism - P-glycoprotein and cytochrome P4503A

被引:41
作者
Christians, U [1 ]
机构
[1] Univ Colorado, Hlth Sci Ctr, Dept Anesthesiol, Clin Res & Dev, Denver, CO 80262 USA
关键词
P-glycoprotein; cytochrome P4503A4; intestinal metabolism;
D O I
10.1097/00007691-200404000-00002
中图分类号
R446 [实验室诊断]; R-33 [实验医学、医学实验];
学科分类号
1001 ;
摘要
Although traditionally the liver was considered the main site of pharmacokinetic drug interactions, this view has been reexamined in light of the finding that cytochrome P4503A4 (CYP3A) enzymes are expressed at high levels in mature villus tip enterocytes. Because of their topographic location in small intestinal enterocytes and their overlap in substrates, functional interactions between P-glycoprotein and CYP3A were suggested. Although the functional interaction between CYP3A and P-glycoprotein is not yet completely understood, experimental evidence suggests several mechanisms: (1) CYP3A and P-glycoprotein are coregulated via the orphan nuclear receptor SXR/PXR; (2) drugs are repeatedly taken up and pumped out of the enterocytes by P-glycoprotein, and repeated exposure to CYP3A enzymes increases the probability of a drug being metabolized; (3) P-glycoprotein keeps intracellular drug concentrations within the linear range of CYP3A enzymes-, (4) metabolism results in better substrates for P-glycoprotein; and (5) metabolism shifts affinity to other intestinal efflux transporters to avoid competitive interaction of metabolites with P-glycoprotein-mediated efflux of the parent drug.
引用
收藏
页码:104 / 106
页数:3
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