A Role for Cytochrome b(5) in the In Vivo Disposition of Anticancer and Cytochrome P450 Probe Drugs in Mice

作者：Henderson Colin J; McLaughlin Lesley A; Finn Robert D; Ronseaux Sebastien; Kapelyukh Yury; Wolf C Roland^*

来源：Drug Metabolism and Disposition, 2014, 42(1): 70-77.

DOI：10.1124/dmd.113.055277

The role of microsomal cytochrome b(5) (Cyb5) in defining the rate of drug metabolism and disposition has been intensely debated for several decades. Recently we described mouse models involving the hepatic or global deletion of Cyb5, demonstrating its central role in in vivo drug disposition. We have now used the cytochrome b(5) complete null (BCN) model to determine the role of Cyb5 in the metabolism of ten pharmaceuticals metabolized by a range of cytochrome P450s, including five anticancer drugs, in vivo and in vitro. The extent to which metabolism was significantly affected by the absence of Cyb5 was substrate-dependent; AUC increased (75-245%) and clearance decreased (35-72%) for phenacetin, metoprolol, and chlorzoxazone. Tolbutamide disposition was not significantly altered by Cyb5 deletion, while for midazolam clearance was decreased by 66%. The absence of Cyb5 had no effect on gefitinib and paclitaxel disposition, while significant changes in the in vivo pharmacokinetics were measured for: cyclophosphamide [maximum plasma concentration (C-max) and terminal half-life increased 55% and 40%, respectively], tamoxifen (AUC(last) and C-max increased 370% and 233%, respectively), and anastrozole (AUC and terminal half-life increased 125% and 62%, respectively; clearance down 80%). These data provide strong evidence that both hepatic and extrahepatic Cyb5 levels are an important determinant of in vivo drug disposition catalyzed by a range of cytochrome P450s, including currently prescribed anticancer agents, and that individuality in Cyb5 expression could be a significant determinant in rates of drug disposition in man.

• 出版日期2014-1