Selective effects of a therapeutic protein targeting tumor necrosis factor-alpha on cytochrome P450 regulation during infectious colitis: implications for disease-dependent drug–drug interactions

• Type of Material: Article
• Authors: Beatrice A Nyagode, Emory University; Roya Jahangardi, Emory University; Matthew D Merrell, Emory University; MariadeLourdes Tansey, Emory University; Edward T Morgan, Emory University
• Language: English
• Date: 2014-02-01
• Publisher: Wiley Open Access: Various Creative Commons Licenses
• Publication Version: Final Published Version
• Copyright Statement: © 2014 The Authors
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1002/prp2.27
• Title of Journal or Parent Work: Pharmacology Research & Perspectives
• ISSN: 2052-1707
• Volume: 2
• Issue: 1
• Start Page: e00027
• End Page: e00027
• Grant/Funding Information: This work was supported by a grant from the National Institutes of Health to E. T. M. (grant R01 DK072372).
• Keywords: Biologics; Therapeutic Proteins; Drug-Drug Interactions; Inflammation; Drug Metabolism; Cytochrome P450
• Research Categories: Biology, Physiology; Health Sciences, Pharmacology

Abstract

We studied the impact of administering XPro1595, a novel antagonist of soluble tumor necrosis factor-α (TNFα), on the regulation of hepatic cytochrome P450 enzymes in the C. rodentium model of infectious colitis. XPro1595 was administered subcutaneously every three days throughout the infection, or as a single injection near the peak of infection. When given throughout the infection, XPro1595 selectively blocked the down-regulation of Cyp3a11 and 3a25 mRNAs, as well as the induction of Cyp2a4/5, without affecting the down-regulation of Cyp4a10, Cyp4a14, Cyp2b10 or flavin-mooxygenase-3. Induction of Cyp3a11, Cyp3a25, Cyp2c29 and Cyp3a13 mRNAs were observed only in XPro1595-treated mice. Administration of a single dose of XPro1595 was relatively ineffective. These results a) confirm the role of soluble TNFα in hepatic Cyp3a regulation during infectious colitis deduced from studies in TNFα receptor-1 knockout mice; b) indicate the potential for soluble TNFα-specific antagonists to cause disease-dependent drug-drug interactions; and, c) suggest a novel mechanism by which an anti-inflammatory therapeutic protein can produce an opposite effect to that of the disease by selectively neutralizing one of multiple signals regulating drug-metabolizing enzyme expression. More research is needed to determine whether or not this is applicable to other diseases or disease models.