Cytokines and Pharmacokinetic Drug Interactions

The expression of cytochrome P450 and P-glycoprotein is altered during the operation of host defense mechanisms. The basis for this interaction is predominantly through cytokine-mediated pathways. Most of the major cytokines, including interleukin (IL)-1α, IL-1β, IL-2β, IL-6, tumor necrosis factor-α, inteferon-α, inteferon-γ, and transforming growth factor-β, are known to downregulate the major forms of cytochrome P450 and P-glycoprotein. In most cases individual cytochrome P450 forms are downregulated at the level of gene transcription, with a resulting decrease in the corresponding messenger ribonucleic acid, protein, and enzyme activity. The cytokine-mediated loss in drug metabolism is channeled predominantly through the modification of specific transcription factors. Similar pathways appear to alter the expression of P-glycoprotein. In clinical medicine, there are numerous examples of a decreased capacity to handle drugs during infections and disease states that involve an inflammatory component and the production of cytokines. The direct administration of cytokines to humans depresses the levels of several cytochrome P450-mediated pathways. The production of cytokines in humans often results in altered drug responses and increased toxicities, which has major implications in inflammation and infection when the capacity of the liver and other organs to handle drugs is severely compromised. Changes in drug-handling capacity during inflammation/infection will continue to be one of the many factors that complicate therapeutics.