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 theC. rodentiummodel 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.
Department of Pharmacology (B.A.N., R.J., M.D.M., E.T.M.) and Department of Physiology (M.G.T), Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA30322, USA.
Beatrice A
BA
Nyagode
Department of Pharmacology (B.A.N., R.J., M.D.M., E.T.M.) and Department of Physiology (M.G.T), Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA30322, USA.
Roya
R
Jahangardi
Department of Pharmacology (B.A.N., R.J., M.D.M., E.T.M.) and Department of Physiology (M.G.T), Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA30322, USA.
Matthew D
MD
Merrell
Department of Pharmacology (B.A.N., R.J., M.D.M., E.T.M.) and Department of Physiology (M.G.T), Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA30322, USA.
Malú G
MG
Tansey
Department of Pharmacology (B.A.N., R.J., M.D.M., E.T.M.) and Department of Physiology (M.G.T), Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA30322, USA.
Edward T
ET
Morgan
Biologics; Cytochrome P450; Drug Metabolism; Drug-Drug Interactions; Inflammation; Therapeutic Proteins