The PREgnane X receptor gene-humanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A.

The PREgnane X receptor gene-humanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A. Research Abstract Details 

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The PREgnane X receptor gene-humanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A. Abstract Text:

Xiaochao Ma,Yatrik Shah,Connie Cheung,Grace L Guo,Lionel Feigenbaum,Kristopher W Krausz,Jeffrey R Idle,Frank J Gonzalez,

The most common clinical implication for the activation of the human pregnane X receptor (PXR) is the occurrence of drug-drug interactions mediated by up-regulated cytochromes P450 3A (CYP3A) isozymes. Typical rodent models do not predict drug-drug interactions mediated by human PXR because of species differences in response to PXR ligands. In the current study, a PXR-humanized mouse model was generated by bacterial artificial chromosome (BAC) transgenesis in Pxr-null mice using a BAC clone containing the complete human PXR gene and 5'- and 3'-flanking sequences. In this PXR-humanized mouse model, PXR is selectively expressed in the liver and intestine, the same tissue expression pattern as CYP3A. Treatment of PXR-humanized mice with the PXR ligands mimicked the human response, since both hepatic and intestinal CYP3As were strongly induced by rifampicin, a human-specific PXR ligand, but not by pregnenolone 16alpha-carbonitrile, a rodent-specific PXR ligand. In rifampicin-pretreated PXR-humanized mice, an approximately 60% decrease was observed for both the maximal midazolam serum concentration (C(max)) and the area under the concentration-time curve, as a result of a 3-fold increase in midazolam 1'-hydroxylation. These results illustrate the potential utility of the PXR-humanized mice in the investigation of drug-drug interactions mediated by CYP3A and suggest that the PXR-humanized mouse model would be an appropriate in vivo tool for evaluation of the overall pharmacokinetic consequences of human PXR activation by drugs.

The PREgnane X receptor gene-humanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A. Publishing Authors By Initials

X Ma,Y Shah,C Cheung,GL Guo,L Feigenbaum,KW Krausz,JR Idle,FJ Gonzalez,

For similar proteins: receptors, cytoplasmic and nuclear: receptors, steroid research abstracts see: proteins: receptors, cytoplasmic and nuclear: receptors, steroid research

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The PREgnane X receptor gene-humanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Intr

Journal: Drug metabolism and disposition: the biological fa

VOLUME: 35

Page Numbers: 194-200

Journal Abbreviation: Drug Metab. Dispos.

ISSN: 0090-9556

DAY: 8

MONTH: 11

YEAR: 2006

The PREgnane X receptor gene-humanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9421550

The PREgnane X receptor gene-humanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A. Keywords Mesh Terms:

KEYWORDS: Receptors, Steroid

MESH TERMS: genetics

Chemical & Substance for Abstract: The PREgnane X receptor gene-humanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A. Information

Substance Name: CYP3A protein, mouse

Registry Number: EC 1.14.14.1

Grant and Affiliation Information for The PREgnane X receptor gene-humanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A.

AFFILIATION: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Country: United States

AGENCY: United States NIAID

GRANT: U19 AI067773-02

ACRONYM: AI

MEDLINETA: Drug Metab Dispos

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