Regional Differences in Human Intestinal Drug Metabolism

Abstract

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, 6b-hydroxytestosterone, 2b-hydroxytestosterone, and 7-HC sulfate were predominantly formed in the ileum, while 15a-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. This work was supported by De Nederlandse organisatie voor gezondheidsonderzoek en zorginnovatie (ZonMW)-The Netherlands [Grant 114025003]. https://doi.org/10.1124/dmd.118.083428.s This article has supplemental material available at dmd.aspetjournals.org.

Inter‐individual and inter‐regional variations in enteric drug metabolizing enzyme activities: Results with cryopreserved human intestinal mucosal epithelia (CHIM) from the small intestines of 14 donors

“…To further define inter‐regional variations, we also evaluated CHIM from ten 12‐inch segments of the first 10 feet of the small intestine (segments A to J) from four additional donors, with the first segment (A) representing the duodenum, and the second to ninth segments (B to I) representing the proximal to distal regions of the jejunum, and the 10th segment (J) representing the proximal region of the ileum. Our results are intended to be complementary to that previously reported by others on enteric drug metabolizing enzymes based on gene expression and proteomics, 34‐37 and drug metabolizing enzyme activity based on human intestinal microsomes, 27,28,35,38‐43 freshly isolated human small intestinal slices, 44 as well as a recent report on the activity of various UGT isoforms in CHIM isolated from various regions of the human small intestine 37 …”

A proximal-to-distal survey of healthy adult human small intestine and colon epithelium by single-cell transcriptomics

“…We explored how medicines might directly affect the intestinal epithelium. While many drugs have GIrelated side effects, few are intended to target the intestinal epithelium itself [156][157][158][159] , and side effects such as diarrhea are often unexplained at the cell-lineage level 160 . We searched for primary targets of all FDA-approved drugs and found 498 approved drugs had 232 primary gene targets expressed in our gut epithelial dataset (Fig.…”

“…While many drugs are metabolized by the liver, oral drugs can be altered by metabolism within the gut epithelium [157][158][159] . We show expression of genes for Phase I and Phase II drug metabolism proteins by lineage with highest expression in the intestinal epithelium (Fig.…”

Age-related changes in intestinal immunity and the microbiome

“…238 While drug metabolism largely takes place in the liver, the small intestine does express CYP450s, including CYP3A4, that eliminate a large proportion of drugs prior to reaching systemic circulation. 239,240 Intestinal expression of CYP3A4 does not appear to change with age in rodents 241 ; however, data are lacking on the expression CYP450 isoforms in the intestine of humans. As the gut microbiota are becoming increasingly recognized as an important contributor to xenobiotic metabolism, 242,243 and since the microbiome changes with age, it will be important for future studies to examine the complex interactions between the host, microbiota, and aging, and their relative contributions to drug metabolism.…”

“…For example, using NSAIDs increases the risk for peptic ulcers by 10% in aged individuals, while combination therapy of corticosteroids and NSAIDs increase the risk of peptic ulcers by 15‐fold 238 . While drug metabolism largely takes place in the liver, the small intestine does express CYP450s, including CYP3A4, that eliminate a large proportion of drugs prior to reaching systemic circulation 239,240 . Intestinal expression of CYP3A4 does not appear to change with age in rodents 241 ; however, data are lacking on the expression CYP450 isoforms in the intestine of humans.…”