Kim R B, Wandel C, Leake B, Cvetkovic M, Fromm M F, Dempsey P J, Roden M M, Belas F, Chaudhary A K, Roden D M, Wood A J, Wilkinson G R
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA.
Pharm Res. 1999 Mar;16(3):408-14. doi: 10.1023/a:1018877803319.
CYP3A and P-gp both function to reduce the intracellular concentration of drug substrates, one by metabolism and the other by transmembrane efflux. Moreover, it has been serendipitously noted that the two proteins have many common substrates and inhibitors. In order to test this notion more fully, systematic studies were undertaken to determine the P-gp-mediated transport and inhibitory characteristics of prototypical CYP substrates.
L-MDR1, LLC-PK1, and Caco-2 cells were used to evaluate established CYP substrates as potential P-gp substrates and inhibitors in vitro, and mdr1a deficient mice were used to assess the in vivo relevance of P-gp-mediated transport.
Some (terfenadine, erythromycin and lovastatin) but not all (nifedipine and midazolam) CYP3A substrates were found to be P-gp substrates. Except for debrisoquine, none of the prototypical substrates of other common human CYP isoforms were transported by P-gp. Studies in mdr1a disrupted mice confirmed that erythromycin was a P-gp substrate but the CYP3A-inhibitor ketoconazole was not. In addition, CYP3A substrates and inhibitors varied widely in their ability to inhibit the P-gp-mediated transport of digoxin.
These results indicate that the overlap in substrate specificities of CYP3A and P-gp appears to be fortuitous rather than indicative of a more fundamental relationship.
细胞色素P450 3A亚家族（CYP3A）和P-糖蛋白（P-gp）均发挥作用以降低药物底物的细胞内浓度，一个通过代谢，另一个通过跨膜外排。此外，偶然发现这两种蛋白有许多共同的底物和抑制剂。为了更全面地验证这一观点，开展了系统研究以确定典型CYP底物的P-gp介导的转运和抑制特性。
使用L-MDR1、LLC-PK1和Caco-2细胞在体外评估已确定的CYP底物作为潜在的P-gp底物和抑制剂，并使用mdr1a基因敲除小鼠评估P-gp介导的转运的体内相关性。
发现一些（特非那定、红霉素和洛伐他汀）但并非所有（硝苯地平和咪达唑仑）CYP3A底物是P-gp底物。除了异喹胍，其他常见人类CYP同工酶的典型底物均未被P-gp转运。对mdr1a基因敲除小鼠的研究证实红霉素是P-gp底物，但CYP3A抑制剂酮康唑不是。此外，CYP3A底物和抑制剂在抑制P-gp介导的地高辛转运的能力上差异很大。
这些结果表明CYP3A和P-gp底物特异性的重叠似乎是偶然的，而非表明存在更根本的关系。
