Plasma levels of TNF-α and IL-6 are inversely related to cytochrome P450-dependent drug metabolism in patients with congestive heart failure

Abstract

Background: Cytochrome P450 (CYP) enzymes are important mediators of drug metabolism, and activity of these enzymes is a major determinant of the duration and intensity of drug effect. Circulating plasma concentrations of pro-inflammatory cytokines (e.g., tumor necrosis factor [TNF]-α and interleukin [IL]-6) are elevated in patients with heart failure and these cytokines have been shown to down-regulate CYP enzyme activity. The purpose of this study was to evaluate the relationship between plasma cytokine concentrations and CYP enzyme activities in patients with heart failure. Methods and Results: Sixteen patients with congestive heart failure (New York Heart Association classes II-IV) received a metabolic probe cocktail consisting of caffeine, mephenytoin, dextromethorphan, and chlorzoxazone to assess the activities of the CYP enzymes 1A2, 2C19, 2D6, and 2E1. Blood and urine samples were collected for drug and metabolite determinations by high-performance liquid chromatography (HPLC); cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA). We found a striking inverse relationship between both TNF-α and IL-6 plasma concentrations and the activity of CYP2C19; metabolism of caffeine (CYP1A2) also had a negative association with IL-6 plasma concentrations. Conclusions: Cytokine-mediated decreases in drug metabolism may contribute to observed variability in drug response and augment the risk of adverse drug effects in CHF patients.