Quantitative Prediction of Human Pregnane X Receptor and Cytochrome P450 3A4 Mediated Drug-Drug Interaction in a Novel Multiple Humanized Mouse Line

TY - JOUR

T1 - Quantitative Prediction of Human Pregnane X Receptor and Cytochrome P450 3A4 Mediated Drug-Drug Interaction in a Novel Multiple Humanized Mouse Line

A1 - Hasegawa,Maki

A1 - Kapelyukh,Yury

A1 - Tahara,Harunobu

A1 - Seibler,Jost

A1 - Rode,Anja

A1 - Krueger,Sylvia

A1 - Lee,Dongtao N.

A1 - Wolf,C. Roland

A1 - Scheer,Nico

AU - Hasegawa,Maki

AU - Kapelyukh,Yury

AU - Tahara,Harunobu

AU - Seibler,Jost

AU - Rode,Anja

AU - Krueger,Sylvia

AU - Lee,Dongtao N.

AU - Wolf,C. Roland

AU - Scheer,Nico

PY - 2011/9

Y1 - 2011/9

N2 - <p>Cytochrome P450 (P450) 3A4 is the predominant P450 enzyme expressed in human liver and intestine, and it is involved in the metabolism of approximately 50% of clinically used drugs. Because of the differences in the multiplicity of CYP3A genes and the poor correlation of substrate specificity of CYP3A proteins between species, the extrapolation of CYP3A-mediated metabolism of a drug from animals to man is difficult. This situation is further complicated by the fact that the predictability of the clinically common drug-drug interaction of pregnane X receptor (PXR)-mediated CYP3A4 induction by animal studies is limited as a result of marked species differences in the interaction of many drugs with this receptor. Here we describe a novel multiple humanized mouse line that combines a humanization for PXR, the closely related constitutive androstane receptor, and a replacement of the mouse Cyp3a cluster with a large human genomic region carrying CYP3A4 and CYP3A7. We provide evidence that this model shows a human-like CYP3A4 induction response to different PXR activators, that it allows the ranking of these activators according to their potency to induce CYP3A4 expression in the human liver, and that it provides an experimental approach to quantitatively predict PXR/CYP3A4-mediated drug-drug interactions in humans.</p>

AB - <p>Cytochrome P450 (P450) 3A4 is the predominant P450 enzyme expressed in human liver and intestine, and it is involved in the metabolism of approximately 50% of clinically used drugs. Because of the differences in the multiplicity of CYP3A genes and the poor correlation of substrate specificity of CYP3A proteins between species, the extrapolation of CYP3A-mediated metabolism of a drug from animals to man is difficult. This situation is further complicated by the fact that the predictability of the clinically common drug-drug interaction of pregnane X receptor (PXR)-mediated CYP3A4 induction by animal studies is limited as a result of marked species differences in the interaction of many drugs with this receptor. Here we describe a novel multiple humanized mouse line that combines a humanization for PXR, the closely related constitutive androstane receptor, and a replacement of the mouse Cyp3a cluster with a large human genomic region carrying CYP3A4 and CYP3A7. We provide evidence that this model shows a human-like CYP3A4 induction response to different PXR activators, that it allows the ranking of these activators according to their potency to induce CYP3A4 expression in the human liver, and that it provides an experimental approach to quantitatively predict PXR/CYP3A4-mediated drug-drug interactions in humans.</p>

KW - CONSTITUTIVE ANDROSTANE RECEPTOR

KW - MAJOR METABOLITES

KW - NUCLEAR RECEPTORS

KW - ENZYME-INDUCTION

KW - HUMAN LIVER

KW - EXPRESSION

KW - PHARMACOKINETICS

KW - RIFAMPIN

KW - CYP3A4

KW - GENE

U2 - 10.1124/mol.111.071845

DO - 10.1124/mol.111.071845

M1 - Article

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 3

VL - 80

SP - 518

EP - 528

ER -