Van Peer Els, Jacobs Frank, Snoeys Jan, Van Houdt Jos, Pijpers Ils, Casteleyn Christophe, Van Ginneken Chris, Van Cruchten Steven
Laboratory of Applied Veterinary Morphology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
Janssen R&D, Beerse, Belgium.
Pharm Res. 2017 Apr;34(4):750-764. doi: 10.1007/s11095-017-2101-y. Epub 2017 Jan 17.
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-Glo assay), 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.
鉴于儿科药物研发，幼年动物研究正变得愈发重要。然而，关于幼年动物药物代谢能力的数据却很匮乏，尤其是在非啮齿类动物中。因此，我们旨在对发育中的哥廷根小型猪肝脏中四种人细胞色素P450（CYP450）底物和一种尿苷二磷酸葡萄糖醛酸转移酶（UGT）底物的体外生物转化进行表征。
将来自胎儿晚期、出生第1天、第3天、第7天、第28天的哥廷根小型猪以及成年雄性和雌性哥廷根小型猪的肝微粒体与CYP450底物混合物一起孵育，该混合物包括非那西丁、甲苯磺丁脲、右美沙芬和咪达唑仑。后者分别是人类CYP1A2、CYP2C9、CYP2D6和CYP3A4的探针底物。此外，UGT多酶底物（来自UGT - Glo检测）也与猪肝微粒体一起孵育，该底物可被几种人UGT1A和UGT2B酶进行葡萄糖醛酸化。
对于所有测试底物，产后药物代谢显著增加。在1月龄时，对乙酰氨基酚和右啡烷形成的活性分别达到成年活性的60.5%和75.4%，而4 - 羟基甲苯磺丁脲和1'-羟基咪达唑仑形成的活性分别为成年活性的35.4%和43.2%。与雄性相比，28日龄和成年雌性中非那西丁的生物转化显著更高。
如在人类中所描述的那样，代谢能力在出生后发生成熟。
