Regional Transcriptomics and Proteomics of Pharmacokinetics-Related Genes in Human Intestine

The intestine is an organ responsible for the absorption
and metabolism
of orally administered drugs. To predict pharmacokinetics behavior
in the small intestine, it is necessary to examine the human intestinal
expression profiles of the genes related to drug absorption, distribution,
metabolism, and excretion (ADME). In this study, to obtain more accurate
expression profiles in various regions of the human intestine, biopsy
samples were collected from endoscopically noninflamed mucosa of the
duodenum, jejunum, ileum, colon, and rectum from Japanese including
Crohn’s disease or ulcerative colitis patients, and both RNA-seq
and quantitative proteomics analyses were performed. We also analyzed
the expression of drug-metabolizing enzymes (cytochromes P450 (CYPs)
and non-CYP enzymes), drug transporters, and nuclear receptors. Overall,
the mRNA expression levels of these ADME-related genes correlated
highly with the protein expression levels. The characteristics of
the expression of ADME-related genes differed significantly between
the small and large intestines, including the expression levels of
CYP enzymes, which were higher and lower in the small and large intestines,
respectively. Most CYPs were expressed dominantly in the small intestine,
especially the jejunum, but were rarely expressed in the large intestine.
On the other hand, non-CYP enzymes were expressed in the large intestine
but at lower expression levels than in the small intestine. Moreover,
the expression levels of drug metabolizing enzyme genes differed even
between the proximal and distal small intestine. Transporters were
expressed most highly in the ileum. The data in the present study
will enhance understanding of the intestinal ADME of drug candidates
and would be useful for drug discovery research.