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

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 Citrobacter rodentium model of infectious colitis. XPro1595 was administered subcutaneously every 3 days throughout the infection, or as a single injection near the peak of infection. When given throughout the infection, XPro1595 selectively blocked the downregulation of Cyp3a11 and 3a25 mRNAs, as well as the induction of Cyp2a4/5, without affecting the downregulation 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 (1) confirm the role of soluble TNFα in hepatic Cyp3a regulation during infectious colitis deduced from studies in TNFα receptor-1 knockout mice; (2) indicate the potential for soluble TNFα -specific antagonists to cause disease-dependent drug–drug interactions; and (3) 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.