Abstract
The induction of cytochrome P450 (P450) enzymes is one of the risk factors for drug-drug interactions (DDIs). To date, the human pregnane X receptor (PXR)-mediated CYP3A4 induction has been well studied. In addition to CYP3A4, the expression of CYP2C subfamily is also regulated by PXR, and the DDIs caused by the induction of CYP2C enzymes have been reported to have a major clinical impact. The purpose of the present study was to investigate whether chimeric mice with a humanized liver (PXB mice) can be a suitable animal model for investigating the PXR-mediated induction of CYP2C subfamily, together with CYP3A4. We evaluated the inductive effect of rifampicin (RIF), a typical human PXR ligand, on the plasma exposure to the four P450 substrate drugs (triazolam/CYP3A4, pioglitazone/CYP2C8, (S)-warfarin/CYP2C9, and (S)-(−)-mephenytoin/CYP2C19) by cassette dosing in PXB mice. The induction of several drug-metabolizing enzymes and transporters in the liver was also examined by measuring the enzyme activity and mRNA expression levels. Significant reductions in the exposure to triazolam, pioglitazone, and (S)-(−)-mephenytoin, but not to (S)-warfarin, were observed. In contrast to the in vivo results, all the four P450 isoforms, including CYP2C9, were elevated by RIF treatment. The discrepancy in the (S)-warfarin results between in vivo and in vitro studies may be attributed to the relatively small contribution of CYP2C9 to (S)-warfarin elimination in the PXB mice used in this study. In summary, PXB mice are a useful animal model to examine DDIs caused by PXR-mediated induction of CYP2C and CYP3A4.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- P450
- cytochrome P450
- DDI
- drug-drug interaction
- PXR
- pregnane X receptor
- MDR
- multidrug resistance gene
- MRP
- multidrug resistance-associated protein
- UGT
- UDP-glucuronosyltransferase
- RIF
- rifampicin
- ROS
- rosiglitazone
- WAR
- (S)-warfarin
- MEP
- (S)-(−)-mephenytoin
- TRZ
- triazolam
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- PCR
- polymerase chain reaction
- G-6-P
- d-glucose 6-phosphate
- G-6-P-DH
- G-6-P dehydrogenase
- LC/MS/MS
- liquid chromatography-tandem mass spectrometry
- AUC
- area under the plasma concentration-time curve.
- Received September 14, 2011.
- Accepted November 29, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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