Inflammatory reactions and drug response: importance of cytochrome P450 and membrane transporters. Issue 5 (September 2008)

• Record Type: Journal Article
• Authors: Dumais, Guillaume; Iovu, Mirela; du Souich, Patrick
• Is Part Of: Expert review of clinical pharmacology. Volume 1:Issue 5(2008)
• Page Start: 627
• Page End: 647
• Publication Date: 2008-09
• Subjects: adverse effects -- ATP-binding cassette transporters -- cardiovascular disease -- cytochrome P450 -- inflammation -- pharmacodynamic -- pharmacokinetic; Clinical pharmacology -- Periodicals; 615.105
• DOI: 10.1586/17512433.1.5.627
• Languages: English
• ISSNs: 1751-2433

Abstract

Inflammatory reactions (IRs), both infectious and aseptic, downregulate numerous enzymes of cytochrome P450 (CYP) and ATP-binding cassette transporters. The mechanism involves proinflammatory cytokines and activation of transcription factors, nuclear factor-κκB, CCAAT-enhancer-binding protein-ββ and c-myc, which bind to negative regulatory elements and/or impede the binding of nuclear receptors to promoter elements. Downregulation of CYP enzymes and transporters modulates the kinetics of a drug, resulting in increased plasma and tissue concentrations of the drug and enhanced effect and/or toxicity. Clinical trials have shown that IRs increase the risk of myocardial infarction and stroke. In this article, we speculate that IRs downregulate cardiac and vascular CYP enzymes (CYP2C8/9 and CYP2J2) responsible for the formation of vasorelaxant products. Patients with IRs should be advised that the risk of drug adverse effects and of cardiovascular diseases is increased; therefore, the benefit–risk ratio and use of drugs with narrow therapeutic index should be revaluated, as well as the conditions precipitating cardiovascular events.