Abstract
The Göttingen 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 Göttingen Minipig. The aim of this study was to assess hepatic cytochrome P450 (CYP) protein abundance in the developing Göttingen 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 Göttingen 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 Göttingen Minipig PBPK model.
Highlights
In recent years, the Göttingen Minipig has gained attention in view of pediatric drug development (Downes, 2018)
Cytochrome P450 (CYP) protein abundance was determined in the developing Göttingen Minipig and
In the adult age groups of the second experiment, statistically significant sex-related differences were observed for CYP1A1, CYP1A2, CYP2A19, CYP2E1_2, CYP3A22, CYP4V2_2a and CYP4V2_2b with highest values observed in female animals for all isoforms (Figure 4)
Summary
The Göttingen Minipig has gained attention in view of pediatric drug development (Downes, 2018). PBPK modeling requires three different sources of information namely i) systemic data based upon the population of interest (e.g. organ weight, blood flow rate, amount of microsomal protein per gram of liver (MPPGL), glomerular filtration rate, ontogeny of drug metabolizing enzymes and transporters (DMET)) ii) drug data (e.g. physicochemical parameters, drug solubility, tissue partitioning, plasma protein binding, drug-drug interactions), and iii) trial design parameters (e.g. dose and dose regimen, route of administration, population size and demographics) (Jamei et al, 2009; Zhuang and Lu, 2016) The integration of these various parameters results in a mathematical model that provides a bottom-up approach to predict drug exposure (Zhuang and Lu, 2016).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
