Hemodialysis acutely improves hepatic CYP3A4 metabolic activity

The uremic syndrome remains poorly understood despite the widespread availability of dialysis for almost four decades. To date, assessment of the biologic activity of uremic toxins has focused primarily on in vitro effects, rather than on specific biochemical pathways or enzymatic activity in vivo. The activity of cytochrome P450 (CYP) 3A4, the most important enzyme in human drug metabolism, is decreased in uremia. The purpose of this study was to assess the effect of hemodialysis and hence varying concentrations of uremic toxins on CYP3A4 activity using the 14C-erythromycin breath test and the traditional phenotypic trait measure, 20-min 14CO2 flux. CYP3A4 activity increased by 27% postdialysis (P = 0.002 compared with predialysis) and was significantly inversely related to plasma blood urea nitrogen concentration (rs= -0.50, P = 0.012), but not to several middle molecules. This is the first study in humans characterizing uremia as a state in which hepatic CYP3A4 activity is acutely improved by hemodialysis.