Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Richard B. Kim

Abstract

Inflammatory bowel disease (IBD) is an illness of chronic intestinal inflammation comprised of Crohn's disease (CD) and ulcerative colitis (UC). Specialists rely heavily on drugs that target a dysregulated immune system. There is a staggering degree of variation in drug response in CD. Our understanding of drug metabolism and response in IBD is limited. Gaining new insights into IBD-specific modifications of drug metabolism may allow for improved drug efficacy and reduced toxicity. Cytochrome P450 (CYP) 3A4 is the most relevant determinant of drug metabolism and exposure for medications prescribed today. CYP3A4 is highly expressed in the liver, but is also important to intestinal drug metabolism. Little is known about CYP3A4 activity in disease states. We tested the hypothesis that CD affects the activity, expression and regulation of CYP3A4. Acute, non-hepatic inflammatory states are reported to reduce hepatic CYP3A4 activity. Using midazolam pharmacokinetics and the cholesterol metabolite, 4β- hydroxycholesterol as in vivo probes of CYP3A4 activity, we were able to demonstrate and confirm that CYP3A4 activity is lower in CD. Conversely, we were unable to show, using in vitro modeling, that differences in CYP3A4 activity were due to differential nuclear receptor-signaling in CD. CYP3A4 plays a key role in hepatic and intestinal first-pass metabolism, likely in concert with the xenobiotic exporter, P-glycoprotein (P-gp). The intestinal and colonic ii expression of CYP3A4 in CD has not been well characterized. Using an immunobloting technique, we were able to demonstrate that the intestinal and colonic expression of CYP3A4 are reduced in CD. Lastly, nuclear receptors such as FXR and PXR are important regulators of CYP3A4. Both are down-regulated in IBD. This may have important consequences for drug response in IBD. We confirm that a novel single nucleotide polymorphism in FXR results in a reduction in its downstream products in vivo and reveal a link between genetic variation in FXR and outcomes of CD severity, such as risk and time to surgery, particularly relevant to women affected by CD. Ultimately, these studies demonstrate the impact of CD on drug metabolism pathways and offer insight into the overlap between CD pathogenesis and drug metabolism.

Available for download on Monday, August 03, 2020

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