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Hepatic cytochrome P450 abundance and activity in the developing and adult Gottingen Minipig : Pivotal data for PBPK modeling

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Abstract
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.
Keywords
DRUG-METABOLIZING-ENZYMES, MESSENGER-RNA EXPRESSION, PROTEIN ABUNDANCE, HUMAN LIVER, DEVELOPMENTAL EXPRESSION, SEX-DIFFERENCES, PIG-LIVER, INTERINDIVIDUAL VARIABILITY, CONSTITUTIVE EXPRESSION, PLASMA-CONCENTRATIONS, CYP, protein abundance, ontogeny, G&#246, ttingen Minipig, pediatrics, mass spectrometry

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MLA
Buyssens, Laura, et al. “Hepatic Cytochrome P450 Abundance and Activity in the Developing and Adult Gottingen Minipig : Pivotal Data for PBPK Modeling.” FRONTIERS IN PHARMACOLOGY, vol. 12, 2021, doi:10.3389/fphar.2021.665644.
APA
Buyssens, L., De Clerck, L., Schelstraete, W., Dhaenens, M., Deforce, D., Ayuso, M., … Van Cruchten, S. (2021). Hepatic cytochrome P450 abundance and activity in the developing and adult Gottingen Minipig : Pivotal data for PBPK modeling. FRONTIERS IN PHARMACOLOGY, 12. https://doi.org/10.3389/fphar.2021.665644
Chicago author-date
Buyssens, Laura, Laura De Clerck, Wim Schelstraete, Maarten Dhaenens, Dieter Deforce, Miriam Ayuso, Chris Van Ginneken, and Steven Van Cruchten. 2021. “Hepatic Cytochrome P450 Abundance and Activity in the Developing and Adult Gottingen Minipig : Pivotal Data for PBPK Modeling.” FRONTIERS IN PHARMACOLOGY 12. https://doi.org/10.3389/fphar.2021.665644.
Chicago author-date (all authors)
Buyssens, Laura, Laura De Clerck, Wim Schelstraete, Maarten Dhaenens, Dieter Deforce, Miriam Ayuso, Chris Van Ginneken, and Steven Van Cruchten. 2021. “Hepatic Cytochrome P450 Abundance and Activity in the Developing and Adult Gottingen Minipig : Pivotal Data for PBPK Modeling.” FRONTIERS IN PHARMACOLOGY 12. doi:10.3389/fphar.2021.665644.
Vancouver
1.
Buyssens L, De Clerck L, Schelstraete W, Dhaenens M, Deforce D, Ayuso M, et al. Hepatic cytochrome P450 abundance and activity in the developing and adult Gottingen Minipig : Pivotal data for PBPK modeling. FRONTIERS IN PHARMACOLOGY. 2021;12.
IEEE
[1]
L. Buyssens et al., “Hepatic cytochrome P450 abundance and activity in the developing and adult Gottingen Minipig : Pivotal data for PBPK modeling,” FRONTIERS IN PHARMACOLOGY, vol. 12, 2021.
@article{8718176,
  abstract     = {{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.}},
  articleno    = {{665644}},
  author       = {{Buyssens, Laura and De Clerck, Laura and Schelstraete, Wim and Dhaenens, Maarten and Deforce, Dieter and Ayuso, Miriam and Van Ginneken, Chris and Van Cruchten, Steven}},
  issn         = {{1663-9812}},
  journal      = {{FRONTIERS IN PHARMACOLOGY}},
  keywords     = {{DRUG-METABOLIZING-ENZYMES,MESSENGER-RNA EXPRESSION,PROTEIN ABUNDANCE,HUMAN LIVER,DEVELOPMENTAL EXPRESSION,SEX-DIFFERENCES,PIG-LIVER,INTERINDIVIDUAL VARIABILITY,CONSTITUTIVE EXPRESSION,PLASMA-CONCENTRATIONS,CYP,protein abundance,ontogeny,G&#246,ttingen Minipig,pediatrics,mass spectrometry}},
  language     = {{eng}},
  pages        = {{15}},
  title        = {{Hepatic cytochrome P450 abundance and activity in the developing and adult Gottingen Minipig : Pivotal data for PBPK modeling}},
  url          = {{http://dx.doi.org/10.3389/fphar.2021.665644}},
  volume       = {{12}},
  year         = {{2021}},
}

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