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Expression of clinically relevant drug‐metabolizing enzymes along the human intestine and their correlation to drug transporters and nuclear receptors: An intra‐subject analysis
Author(s) -
Fritz Anja,
Busch Diana,
Lapczuk Joanna,
Ostrowski Marek,
Drozdzik Marek,
Oswald Stefan
Publication year - 2019
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.13137
Subject(s) - ileum , jejunum , pregnane x receptor , small intestine , drug metabolism , duodenum , pharmacology , transporter , drug , nuclear receptor , receptor , pharmacokinetics , cyp3a4 , chemistry , biology , metabolism , cytochrome p450 , biochemistry , medicine , gene , transcription factor
The oral bioavailability of many drugs is highly influenced not only by hepatic but also by intestinal biotransformation. To estimate the impact of intestinal phase I and II metabolism on oral drug absorption, knowledge on the expression levels of the respective enzymes is an essential prerequisite. In addition, the potential interplay of metabolism and transport contributes to drug disposition. Both mechanisms may be subjected to coordinative regulation by nuclear receptors, leading to unwanted drug‐drug interactions due to induction of intestinal metabolism and transport. Thus, it was the aim of this study to comprehensively analyse the regional expression of clinically relevant phase I and II enzymes along the entire human intestine and to correlate these data to expression data of drug transporters and nuclear receptors of pharmacokinetic relevance. Gene expression of 11 drug‐metabolizing enzymes ( CYP 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5, SULT 1A, UGT 1A, UGT 2B7, UGT2B15) was studied in duodenum, jejunum, ileum and colon from six organ donors by real‐time RT ‐ PCR . Enzyme expression was correlated with expression data of the nuclear receptors PXR , CAR and FXR as well as drug transporters observed in the same cohort. Intestinal expression of all studied metabolizing enzymes was significantly higher in the small intestine compared to colonic tissue. CYP 2B6, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A4/5, SULT 1A, UGT 1A and UGT 2B7 expression increased from the duodenum to jejunum but was markedly lower in the ileum. In the small intestine, that is, the predominant site of drug absorption, the highest expression has been observed for CYP 3A4, CYP 2C9, SULT 1A and UGT 1A. In addition, significant correlations were found between several enzymes and PXR as well as ABC transporters in the small intestine. In conclusion, the observed substantial site‐dependent intestinal expression of several enzymes may explain regional differences in intestinal drug absorption. The detected correlations between intestinal enzymes, transporters and nuclear receptors provide indirect evidence for their coordinative expression, regulation and function in the human small intestine.