@article{StanleyHorsburghRossetal.2006,
  author    = {Stanley, Lesley A. and Horsburgh, Brian C. and Ross, Jillian and Scheer, Nico and Wolf, C. Roland},
  title     = {Nuclear Receptors which play a pivotal role in drug disposition and chemical toxicity},
  series = {Drug Metabolism Reviews},
  volume    = {38},
  journal   = {Drug Metabolism Reviews},
  number    = {3},
  issn      = {1097-9883},
  doi       = {10.1080/03602530600786232},
  pages     = {515 -- 597},
  year      = {2006},
  language  = {en}
}
@article{WilsonDickieSchreiteretal.2018,
  author    = {Wilson, C. E. and Dickie, A. P. and Schreiter, K. and Wehr, R. and Wilson, E. M. and Bial, J. and Scheer, Nico and Wilson, I. D. and Riley, R. J.},
  title     = {The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice},
  series = {Archives of Toxicology},
  volume    = {92},
  journal   = {Archives of Toxicology},
  number    = {6},
  publisher = {Springer},
  issn      = {1432-0738},
  doi       = {10.1007/s00204-018-2212-1},
  pages     = {1953 -- 1967},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}
@article{WilsonWilsonScheeretal.2017,
  author    = {Wilson, Ian D. and Wilson, Claire E. and Scheer, Nico and Dickie, A.P. and Schreiter, K. and Wilson, E. M. and Riley, R. J. and Wehr, R. and Bial, J.},
  title     = {The Pharmacokinetics and Metabolism of Lumiracoxib in Chimeric Humanized and Murinized FRG Mice},
  series = {Biochemical pharmacology},
  volume    = {Volume 135},
  journal   = {Biochemical pharmacology},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {1873-2968},
  doi       = {10.1016/j.bcp.2017.03.015},
  pages     = {139 -- 150},
  year      = {2017},
  language  = {en}
}
@article{ZhangHeimbachScheeretal.2016,
  author    = {Zhang, Jin and Heimbach, Tycho and Scheer, Nico and Barve, Avantika and Li, Wenkui and Lin, Wen and He, Handan},
  title     = {Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4-Humanized Mouse Studies With PBPK Modeling},
  series = {Journal of Pharmaceutical Sciences},
  volume    = {Volume 105},
  journal   = {Journal of Pharmaceutical Sciences},
  number    = {Issue 4},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {0022-3549},
  doi       = {doi.org/10.1016/j.xphs.2016.01.021},
  pages     = {1398 -- 1404},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}