کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2481760 1556267 2008 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Identification of interspecies difference in efflux transporters of hepatocytes from dog, rat, monkey and human
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی اکتشاف دارویی
پیش نمایش صفحه اول مقاله
Identification of interspecies difference in efflux transporters of hepatocytes from dog, rat, monkey and human
چکیده انگلیسی

The large interspecies differences of hepatobiliary transport present a challenge for the allometric prediction of human biliary excretion for drug candidates primarily cleared via hepatobiliary secretion. In the present study, we determined the metabolic stabilities of common fluorescent substrates of hepatobiliary efflux transporters and developed a rapid efflux assay to determine the functional activities of MRP/Mrp, BCRP/Bcrp and P-gp in hepatocytes of four species. The specificities of transporter-mediated dye efflux were confirmed by selective transporter inhibitors. Among tested species, transporter-specific dye efflux kinetics was consistent between freshly isolated and cryopreserved hepatocytes. Hepatocyte elimination half-lives of MRP/Mrp substrates GS-MF and calcein were observed in the rank order of human > monkey > dog > rat. The fourfold higher MRP/Mrp substrate efflux rate of rat hepatocytes compared to human is likely due to the species-specific functional differences of MRP2/Mrp2 expressed on the canalicular membrane. We also observed efficient BCRP-mediated pheophorbide A (PhA) efflux by human and dog hepatocytes, while PhA extrusion in monkey and rat hepatocytes appeared limited. P-gp function measured by DiOC2(3) efflux was minimal in hepatocytes of all origins and no significant species differences were detected. Our results demonstrated marked differences in hepatocyte MRP/Mrp and BCRP/Bcrp activities across species, indicating that they may contribute to the species differences of in vivo hepatobiliary excretion. These results also suggest the potential utility of primary hepatocytes, either fresh or cryopreserved, as an in vitro model to predict interspecies differences in the biliary transport of MRP/Mrp and BCRP/Bcrp substrates.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmaceutical Sciences - Volume 35, Issues 1–2, 2 September 2008, Pages 114–126
نویسندگان
, , , , , , , , , ,