An Update On The Role Of Intestinal Cytochrome P450 Enzymes In Drug Disposition
Authors: Fang Xie, Xinxin Ding, Qing-Yu Zhang
Abstract:
The most commonly utilized method for drug treatment is through oral administration. However, when drugs are taken orally, a significant portion of them can be eliminated by the metabolic activity of intestinal cytochrome P450 (CYP) enzymes before they enter systemic circulation. Interestingly, some drugs can bypass this metabolism and proceed through the intestinal passage unaffected. To enhance the effectiveness and availability of existing drugs as well as those in development, it is crucial to gain a deeper understanding of how intestinal P450 enzymes metabolize different clinical drugs in humans and preclinical animal models. This understanding involves identifying the specific CYP enzymes expressed in the intestine, studying their regulation, and determining the relative significance of intestinal metabolism compared to hepatic metabolism.
In this review, we provide a concise overview of the expression patterns of drug-metabolizing P450 enzymes in the small intestine of both humans and various preclinical animal species. Additionally, we discuss the factors and events that influence the expression of intestinal P450 enzymes, including the communication between the liver and the intestine. Furthermore, we compare different clinical and preclinical methods used to evaluate the impact of intestinal drug metabolism on bioavailability. Lastly, we delve into the usefulness of a mouse model called the intestinal epithelium–specific NADPH-cytochrome P450 reductase-null (IECN) mouse, which specifically lacks the NADPH-cytochrome P450 reductase enzyme in the intestinal epithelium. This model serves as a valuable tool for studying the in vivo roles of intestinal P450 enzymes in the processing of orally administered drugs.
Keywords
Cytochrome P450; Intestine; Bioavailability; Drug disposition; Drug metabolism
Citation: Fang Xie, Xinxin Ding, Qing-Yu Zhang An Update On The Role Of Intestinal Cytochrome P450 Enzymes In Drug Disposition doi:10.1016/j.apsb.2016.07.012
Received: 28 April 2016, Revised: 12 July 2016, Accepted: 14 July 2016, Available online: 4 August 2016
Copyright: © 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Acknowledgment
This work was supported in part by grants from the U. S. National Institutes of Health (CA092596, ES020867, and GM082978).
