Investigating the role of CAR and PXR in the regulation of cytochrome P450s and other drug metabolising enzymes by anti-cancer drugs using novel humanised mouse models

摘要

Nuclear receptor activation, particularly that of the pregnane X receptor (PXR) and constitutive androstane receptor (CAR), is increasingly recognised as a keydeterminant in the development of drug-drug interactions (DDIs) as a result oftheir key role in the transcriptional regulation of numerous drug metabolizingenzymes and drug transporters. PXR and CAR involvement in the regulation of the cytochrome P450 enzymes is of greatest concern, since these enzymes metabolise the majority of currently available therapeutics. Various methods are available to investigate the activation of these receptors in response to drug challenge, including reporter gene assays, primary human hepatocytes and transgenic mouse models. However, these models lack the sophistication to effectively assess receptor cross-talk, a key regulatory mechanism in the control of drug metabolism with the potential to impact the development of DDIs. Using a novel panel of PXR & CAR transgenic mouse models this study was designed to investigate the role of cross-talk between PXR and CAR in the metabolism and pharmacokinetics of commonly available pharmaceuticals, with particular emphasis on species-specific regulation.This study has identified potential interactions with PXR and CAR following treatment of wild-type mice with cyclophosphamide, gefitinib, anastrozole andletrozole. Data from the PXR/CAR transgenic mouse panel has also providedevidence that the aromatase inhibitors, anastrozole and letrozole, interact with PXR and CAR in a species- and gender-specific manner. Cross-talk between these receptors plays a key role in the regulation of P450 expression and drugpharmacokinetics following treatment by these agents, although the elimination of these drugs appears to be primarily renal, in contrast to data derived from humans. Of particular note is the aromatase inhibitor-induced up-regulation of Cyp2b10 expression and activity observed in all models possessing a functional CAR moiety. A corresponding induction in CYP2B6 transcriptional activation has been confirmed in a novel reporter mouse model, indicating a potential DDI risk if coadministered with a drug requiring CYP2B6 for its metabolism, i.e.cyclophosphamide. These data therefore support the use of these models as a tool to dissect the regulatory cross-talk of these receptors in the control of drug metabolism, and thus to improve the assessment of DDI risk in the development of therapeutics.