About this item:

585 Views | 565 Downloads

Author Notes:

Correspondence: Edward T. Morgan, Department of Pharmacology, Emory University School of Medicine, 5119 Rollins Research Center, 1510 Clifton Road, Atlanta, GA 30322. Telephone: (404) 727-5986. Fax: (404) 727-0365. Email: etmorga@emory.edu.

B. A. Nyagode, R. Jahangardi, and M. D.Merrell contributed equally to this work.

We are grateful to Xencor, Inc., for supplying the XPro1595, and to David Szymkowsk of Xencor, Inc., for insightful comments on the manuscript.

M. G. Tansey is coinventor of the dominant-negative TNF inhibitors and an ex-employee of Xencor Inc. She does not hold significant financial stake in the company and is not a consultant.

Subjects:

Research Funding:

This work was supported by a grant from the National Institutes of Health to E. T. M. (grant R01 DK072372).

Keywords:

  • Biologics
  • Cytochrome P450
  • Drug Metabolism
  • Drug-Drug Interactions
  • Inflammation
  • Therapeutic Proteins

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

Tools:

Journal Title:

Pharmacology Research & Perspectives

Volume:

Volume 2, Number 1

Publisher:

, Pages e00027-e00027

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2014 The Authors

This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported License ( http://creativecommons.org/licenses/by/3.0/), which permits distribution of derivative works, making multiple copies, distribution, public display, and publicly performance, provided the original work is properly cited. This license requires credit be given to copyright holder and/or author, copyright and license notices be kept intact.

Creative Commons License

Export to EndNote