TY  - JOUR
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
T1  - Quantitative prediction of human pregnane X receptor and cytochrome P450 3A4 mediated drug-drug interaction in a novel multiple humanized mouse line
JF  - Molecular Pharmacology
Y1  - 2011
U6  - http://dx.doi.org/10.1124/mol.111.071845
SN  - 1521-0111
VL  - 80
IS  - 33
SP  - 518
EP  - 528
PB  - ASPET
CY  - Bethesda, Md.
ER  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Snaith, Mike
A1  - Wolf, C. Roland
A1  - Seibler, Jost
T1  - Generation and utility of genetically humanized mouse models
JF  - Drug Discovery Today
Y1  - 2013
U6  - http://dx.doi.org/10.1016/j.drudis.2013.07.007
SN  - 1359-6446
VL  - Vol 18
IS  - 23-24
SP  - 1200
EP  - 1211
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Wilson, C. E.
A1  - Dickie, A. P.
A1  - Schreiter, K.
A1  - Wehr, R.
A1  - Wilson, E. M.
A1  - Bial, J.
A1  - Scheer, Nico
A1  - Wilson, I. D.
A1  - Riley, R. J.
T1  - The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice
JF  - Archives of Toxicology
N2  - The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9 µg/mL (n = 3) at 0.25 h post-dose with an AUCinf of 3.67 µg h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31 µg/mL at 0.25 h post-dose with an AUCinf of 4.94 ± 2.93 µg h/mL and a half-life of 0.52 ± 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53 µg/mL were seen 0.25 h post-dose with a mean AUCinf of 2.10 ± 0.49 µg h/mL and a half-life of 0.51 ± 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may represent a model for assessing the biotransformation of such compounds in humans.
Y1  - 2018
U6  - http://dx.doi.org/10.1007/s00204-018-2212-1
SN  - 1432-0738
VL  - 92
IS  - 6
SP  - 1953
EP  - 1967
PB  - Springer
ER  - 
TY  - JOUR
A1  - Wilson, Ian D.
A1  - Wilson, Claire E.
A1  - Scheer, Nico
A1  - Dickie, A.P.
A1  - Schreiter, K.
A1  - Wilson, E. M.
A1  - Riley, R. J.
A1  - Wehr, R.
A1  - Bial, J.
T1  - The Pharmacokinetics and Metabolism of Lumiracoxib in Chimeric Humanized and Murinized FRG Mice
JF  - Biochemical pharmacology
Y1  - 2017
U6  - http://dx.doi.org/10.1016/j.bcp.2017.03.015
SN  - 1873-2968
VL  - Volume 135
SP  - 139
EP  - 150
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Zhang, Jin
A1  - Heimbach, Tycho
A1  - Scheer, Nico
A1  - Barve, Avantika
A1  - Li, Wenkui
A1  - Lin, Wen
A1  - He, Handan
T1  - Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4–Humanized Mouse Studies With PBPK Modeling
JF  - Journal of Pharmaceutical Sciences
N2  - NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (ƒₘCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate ƒₘCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human ƒₘCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir.
Y1  - 2016
U6  - http://dx.doi.org/doi.org/10.1016/j.xphs.2016.01.021
SN  - 0022-3549
VL  - Volume 105
IS  - Issue 4
SP  - 1398
EP  - 1404
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Dallas, Shannon
A1  - Salphati, Laurent
A1  - Gomez-Zepeda, David
A1  - Wanek, Thomas
A1  - Chen, Liangfu
A1  - Chu, Xiaoyan
A1  - Kunta, Jeevan
A1  - Mezler, Mario
A1  - Menet, Marie-Claude
A1  - Chasseigneaux, Stephanie
A1  - Declèves, Xavier
A1  - Langer, Oliver
A1  - Pierre, Esaie
A1  - DiLoreto, Karen
A1  - Hoft, Carolin
A1  - Laplanche, Loic
A1  - Pang, Jodie
A1  - Pereira, Tony
A1  - Andonian, Clara
A1  - Simic, Damir
A1  - Rode, Anja
A1  - Yabut, Jocelyn
A1  - Zhang, Xiaolin
A1  - Scheer, Nico
T1  - Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model
JF  - Molecular Pharmacology
N2  - Breast cancer resistance protein (BCRP) is expressed in various tissues, such as the gut, liver, kidney and blood brain barrier (BBB), where it mediates the unidirectional transport of substrates to the apical/luminal side of polarized cells. Thereby BCRP acts as an efflux pump, mediating the elimination or restricting the entry of endogenous compounds or xenobiotics into tissues and it plays important roles in drug disposition, efficacy and safety. Bcrp knockout mice (Bcrp−/−) have been used widely to study the role of this transporter in limiting intestinal absorption and brain penetration of substrate compounds. Here we describe the first generation and characterization of a mouse line humanized for BCRP (hBCRP), in which the mouse coding sequence from the start to stop codon was replaced with the corresponding human genomic region, such that the human transporter is expressed under control of the murine Bcrp promoter. We demonstrate robust human and loss of mouse BCRP/Bcrp mRNA and protein expression in the hBCRP mice and the absence of major compensatory changes in the expression of other genes involved in drug metabolism and disposition. Pharmacokinetic and brain distribution studies with several BCRP probe substrates confirmed the functional activity of the human transporter in these mice. Furthermore, we provide practical examples for the use of hBCRP mice to study drug-drug interactions (DDIs). The hBCRP mouse is a promising model to study the in vivo role of human BCRP in limiting absorption and BBB penetration of substrate compounds and to investigate clinically relevant DDIs involving BCRP.
Y1  - 2016
U6  - http://dx.doi.org/10.1124/mol.115.102079
SN  - 1521-0111
VL  - 89
IS  - 5
SP  - 492
EP  - 504
PB  - ASPET
CY  - Bethesda, Md.
ER  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Kapelyukh, Yury
A1  - Rode, Anja
A1  - Oswald, Stefan
A1  - Busch, Diana
A1  - Mclaughlin, Lesley A.
A1  - Lin, De
A1  - Henderson, Colin J.
A1  - Wolf, C. Roland
T1  - Defining Human Pathways of Drug Metabolism In Vivo through the Development of a Multiple Humanized Mouse Model
JF  - Drug Metabolism and Disposition
Y1  - 2015
U6  - http://dx.doi.org/10.1124/dmd.115.065656
SN  - 1521-009x
VL  - 43
IS  - 11
SP  - 1679
EP  - 1690
PB  - ASPET
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Hough, Lindsay B.
A1  - Nalwalk, Julia W.
A1  - Ding, Xinxin
A1  - Scheer, Nico
T1  - Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia-Relevant Isoforms
JF  - Drug Metabolism and Disposition
Y1  - 2015
U6  - http://dx.doi.org/10.1124/dmd.115.065490
SN  - 1521-009x
VL  - 43
IS  - 9
SP  - 1326
EP  - 1330
ER  - 
TY  - JOUR
A1  - Henderson, Colin J.
A1  - Mclaughlin, Lesley A.
A1  - Scheer, Nico
A1  - Stanley, Lesley A.
A1  - Wolf, C. Roland
T1  - Cytochrome b5 Is a Major Determinant of Human Cytochrome P450 CYP2D6 and CYP3A4 Activity In Vivo s
JF  - Molecular Pharmacology
Y1  - 2015
U6  - http://dx.doi.org/10.1124/mol.114.097394
SN  - 1521-0111
VL  - 87
IS  - 4
SP  - 733
EP  - 739
PB  - ASPET
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Luisier, Raphaëlle
A1  - Lempiäinen, Harri
A1  - Scherbichler, Nina
A1  - Braeuning, Albert
A1  - Geissler, Miriam
A1  - Dubost, Valerie
A1  - Müller, Arne
A1  - Scheer, Nico
A1  - Chibout, Salah-Dine
A1  - Hara, Hisanori
A1  - Picard, Frank
A1  - Theil, Diethilde
A1  - Couttet, Philippe
A1  - Vitobello, Antonio
A1  - Grenet, Olivier
A1  - Grasl-Kraupp, Bettina
A1  - Ellinger-Ziegelbauer, Heidrung
A1  - Thomson, John P.
A1  - Meehan, Richard R.
A1  - Elcombe, Clifford R.
A1  - Henderson, Colin J.
A1  - Wolf, C. Roland
A1  - Schwarz, Michael
A1  - Moulin, Pierre
A1  - Terranova, Remi
A1  - Moggs, Jonathan G.
T1  - Phenobarbital Induces Cell Cycle Transcriptional Responses in Mouse Liver Humanized for Constitutive Androstane and Pregnane X Receptors
JF  - Toxicological Sciences
N2  - The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARᴷᴼ-PXRᴷᴼ), double humanized CAR and PXR (CARʰ-PXRʰ), and wild-type C57BL/6 mice. Wild-type and CARʰ-PXRʰ mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absent in CARᴷᴼ-PXRᴷᴼ mouse livers and largely reversible in wild-type and CARʰ-PXRʰ mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARʰ-PXRʰ mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.
Y1  - 2014
U6  - http://dx.doi.org/https://doi.org/10.1093/toxsci/kfu038
SN  - 1094-2025
VL  - 139
IS  - 2
SP  - 501
EP  - 511
PB  - Oxford University Press
CY  - Oxford
ER  -