PMID- 33935788
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210504
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 12
DP  - 2021
TI  - Hepatic Cytochrome P450 Abundance and Activity in the Developing and Adult 
      Gottingen Minipig: Pivotal Data for PBPK Modeling.
PG  - 665644
LID - 10.3389/fphar.2021.665644 [doi]
LID - 665644
AB  - The Gottingen Minipig is gaining ground as nonrodent species in safety testing of 
      drugs for pediatric indications. Due to developmental changes in pharmacokinetics 
      and pharmacodynamics, physiologically based pharmacokinetic (PBPK) models are 
      built to better predict drug exposure in children and to aid species selection 
      for nonclinical safety studies. These PBPK models require high quality 
      physiological and ADME data such as protein abundance of drug metabolizing 
      enzymes. These data are available for man and rat, but scarce for the Gottingen 
      Minipig. The aim of this study was to assess hepatic cytochrome P450 (CYP) 
      protein abundance in the developing Gottingen Minipig by using mass spectrometry. 
      In addition, sex-related differences in CYP protein abundance and correlation of 
      CYP enzyme activity with CYP protein abundance were assessed. The following age 
      groups were included: gestational day (GD) 84-86 (n = 8), GD 108 (n = 6), 
      postnatal day (PND) 1 (n = 8), PND 3 (n = 8), PND 7 (n = 8), PND 28 (n = 8) and 
      adult (n = 8). Liver microsomes were extracted and protein abundance was compared 
      to that in adult animals. Next, the CYP protein abundance was correlated to CYP 
      enzyme activity in the same biological samples. In general, CYP protein abundance 
      gradually increased during development. However, we observed a stable protein 
      expression over time for CYP4A24 and CYP20A1 and for CYP51A1, a high protein 
      expression during the fetal stages was followed by a decrease during the first 
      month of life and an increase toward adulthood. Sex-related differences were 
      observed for CYP4V2_2a and CYP20A1 at PND 1 with highest expression in females 
      for both isoforms. In the adult samples, sex-related differences were detected 
      for CYP1A1, CYP1A2, CYP2A19, CYP2E1_2, CYP3A22, CYP4V2_2a and CYP4V2_2b with 
      higher values in female compared to male Gottingen Minipigs. The correlation 
      analysis between CYP protein abundance and CYP enzyme activity showed that 
      CYP3A22 protein abundance correlated clearly with the metabolism of midazolam at 
      PND 7. These data are remarkably comparable to human data and provide a valuable 
      step forward in the construction of a neonatal and juvenile Gottingen Minipig 
      PBPK model.
CI  - Copyright (c) 2021 Buyssens, De Clerck, Schelstraete, Dhaenens, Deforce, Ayuso, Van 
      Ginneken and Van Cruchten.
FAU - Buyssens, Laura
AU  - Buyssens L
AD  - Comparative Perinatal Development, Department of Veterinary Sciences, Faculty of 
      Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, 
      Wilrijk, Belgium.
FAU - De Clerck, Laura
AU  - De Clerck L
AD  - Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutics, Faculty 
      of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
FAU - Schelstraete, Wim
AU  - Schelstraete W
AD  - Laboratory of Pharmacology and Toxicology, Department of Pharmacology, Toxicology 
      and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, 
      Belgium.
FAU - Dhaenens, Maarten
AU  - Dhaenens M
AD  - Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutics, Faculty 
      of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
FAU - Deforce, Dieter
AU  - Deforce D
AD  - Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutics, Faculty 
      of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
FAU - Ayuso, Miriam
AU  - Ayuso M
AD  - Comparative Perinatal Development, Department of Veterinary Sciences, Faculty of 
      Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, 
      Wilrijk, Belgium.
FAU - Van Ginneken, Chris
AU  - Van Ginneken C
AD  - Comparative Perinatal Development, Department of Veterinary Sciences, Faculty of 
      Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, 
      Wilrijk, Belgium.
FAU - Van Cruchten, Steven
AU  - Van Cruchten S
AD  - Comparative Perinatal Development, Department of Veterinary Sciences, Faculty of 
      Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, 
      Wilrijk, Belgium.
LA  - eng
PT  - Journal Article
DEP - 20210415
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC8082684
OTO - NOTNLM
OT  - CYP
OT  - Gottingen Minipig
OT  - mass spectrometry
OT  - ontogeny
OT  - pediatrics
OT  - protein abundance
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/05/04 06:00
MHDA- 2021/05/04 06:01
PMCR- 2021/04/15
CRDT- 2021/05/03 06:10
PHST- 2021/02/08 00:00 [received]
PHST- 2021/02/26 00:00 [accepted]
PHST- 2021/05/03 06:10 [entrez]
PHST- 2021/05/04 06:00 [pubmed]
PHST- 2021/05/04 06:01 [medline]
PHST- 2021/04/15 00:00 [pmc-release]
AID - 665644 [pii]
AID - 10.3389/fphar.2021.665644 [doi]
PST - epublish
SO  - Front Pharmacol. 2021 Apr 15;12:665644. doi: 10.3389/fphar.2021.665644. 
      eCollection 2021.