RT Journal Article
SR Electronic
T1 Regional Differences in Human Intestinal Drug Metabolism
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1879
OP 1885
DO 10.1124/dmd.118.083428
VO 46
IS 12
A1 Raditya Iswandana
A1 Marina I. Irianti
A1 Dorenda Oosterhuis
A1 Hendrik S. Hofker
A1 Marjolijn T. Merema
A1 Marina H. de Jager
A1 Henricus A. M. Mutsaers
A1 Peter Olinga
YR 2018
UL http://dmd.aspetjournals.org/content/46/12/1879.abstract
AB The intestines are key for the absorption of nutrients and water as well as drug metabolism, and it is well known that there are clear differences in the expression profile of drug metabolism enzymes along the intestinal tract. Yet only a few studies have thoroughly investigated regional differences in human intestinal drug metabolism. In this study, we evaluated phase I and phase II metabolism in matched human ileum and colon precision-cut intestinal slices (PCIS). To this end, human PCIS were incubated for 3 hours with testosterone and 7-hydroxycoumarin (7-HC) to examine phase I and phase II metabolism, respectively. Metabolite formation was assessed by high-performance liquid chromatography analysis. Our results demonstrated that androstenedione, 6β-hydroxytestosterone, 2β-hydroxytestosterone, and 7-HC sulfate were predominantly formed in the ileum, while 15α-hydroxytestosterone and 7-HC glucuronide were mainly produced in the colon. Moreover, we also observed sex differences in phase II metabolite formation, which appeared to be higher in men compared with women. Taken together, we demonstrated that phase I metabolism predominantly occurs in ileum PCIS, while phase II metabolism mostly takes place in colon PCIS. Moreover, we revealed that human PCIS can be used to study both regional and sex differences in intestinal metabolism.