title: In vitro Phase I- and Phase II-Drug Metabolism in The Liver of Juvenile and Adult Göttingen Minipigs.
abstract: In view of pediatric drug development, juvenile animal studies are gaining importance. However, data on drug metabolizing capacities of juvenile animals are scarce, especially in non-rodent species. Therefore, we aimed to characterize the in vitro biotransformation of four human CYP450 substrates and one UGT substrate in the livers of developing Göttingen minipigs.
  
  
  
  Liver microsomes from late fetal, Day 1, Day 3, Day 7, Day 28, and adult male and female Göttingen minipigs were incubated with a cocktail of CYP450 substrates, including phenacetin, tolbutamide, dextromethorphan, and midazolam. The latter are probe substrates for human CYP1A2, CYP2C9, CYP2D6, and CYP3A4, respectively. In addition, the UGT multienzyme substrate (from the UGT-GloTMassay), which is glucuronidated by several human UGT1A and UGT2B enzymes, was also incubated with the porcine liver microsomes.
  
  
  
  For all tested substrates, drug metabolism significantly rose postnatally. At one month of age, 60.5 and 75.4% of adult activities were observed for acetaminophen and dextrorphan formations, respectively, while 35.4 and 43.2% of adult activities were present for 4-OH-tolbutamide and 1'-OH-midazolam formations. Biotransformation of phenacetin was significantly higher in 28-day-old and adult females compared with males.
  
  
  
  Maturation of metabolizing capacities occurred postnatally, as described in man.
authors.affiliation: Laboratory of Applied Veterinary Morphology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Van Peer
authors.affiliation: Janssen R&D, Beerse, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Jacobs
authors.affiliation: Janssen R&D, Beerse, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Snoeys
authors.affiliation: Janssen R&D, Beerse, Belgium.
authors.forename: Jos
authors.initials: J
authors.lastname: Van Houdt
authors.affiliation: Janssen R&D, Beerse, Belgium.
authors.forename: Ils
authors.initials: I
authors.lastname: Pijpers
authors.affiliation: Laboratory of Applied Veterinary Morphology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Casteleyn
authors.affiliation: Laboratory of Applied Veterinary Morphology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: Chris
authors.initials: C
authors.lastname: Van Ginneken
authors.affiliation: Laboratory of Applied Veterinary Morphology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium. steven.vancruchten@uantwerpen.be.
authors.forename: Steven
authors.initials: S
authors.lastname: Van Cruchten
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism; D005260:Female; D005333:Fetus; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D008297:Male; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D008862:Microsomes, Liver / Q000378:metabolism*; D008874:Midazolam / Q000378:metabolism; D010615:Phenacetin / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D014044:Tolbutamide / Q000378:metabolism; D000099148:UGT1A1 Enzyme
chemical_list: D003577:Cytochrome P-450 Enzyme System; D003915:Dextromethorphan; D014453:Glucuronosyltransferase; D008874:Midazolam; D010615:Phenacetin; D014044:Tolbutamide; D000099148:UGT1A1 Enzyme
keywords: CYP450; UGT; development; liver; minipig