CYP3A4, CYP3A5, and MDR1 in human small and large intestinal cell lines suitable for drug transport studies

摘要: ABSTRACT The aim of this study was to find a cell culture model the intestinal epithelium for use in studies CYP3A4-mediated first-pass metabolism drugs and also interplay between CYP3A4 P-glycoprotein efflux. For purpose, expression CYP3A4, CYP3A5, MDR1 mRNA studied three lines normal human transformed colonic (Caco-2) origin. Surprisingly, only were induced by 1α,25-dihydroxy vitamin D 3 (D3) express high amounts CYP3A4. In contrast original findings model, monolayer integrity maintained during D3 treatment. Levels CYP3A Caco-2 TC7 cells differed dramatically. highest levels lowest CYP3A5 observed treated passage numbers, resulting CYP3A4/3A5 ratio greater than fourfold higher that seen cells. Functional studies, using probe testosterone, showed activity completely absent uninduced After induction, metabolite produced both (149.4 ± 12.3 86.5 ± 3.8 pmol 6β-OH testosterone/min/mg cellular protein from 75 μM testosterone cells, respectively). maximum velocity ( V max ) apparent Michaelis constant K m 6β-hydroxylation intact monolayers similar those obtained microsomes. Only minor changes when metabolically stable substrate celiprolol used. conclusion, these results show features generally available line American Type Culture Collection make it suitable drug efflux mechanisms.