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Hemodialysis Acutely Improves Hepatic CYP3A4 Metabolic Activity

Thomas D. Nolin^*,,,, Kofi Appiah^*,, Scott A. Kendrick, Phuong Le, Ellen McMonagle and Jonathan Himmelfarb^*,,

^* Division of Nephrology and Transplantation; Department of Internal Medicine; Department of Pharmacy Services, Maine Medical Center, Portland, Maine; and Division of Nephrology, Maine Medical Center Research Institute, Scarborough, Maine

Address correspondence to: Dr. Jonathan Himmelfarb, Division of Nephrology and Transplantation, Department of Medicine, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102. Phone: 207-662-2417; Fax: 207-662-6306; himmej{at}mmc.org

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 (r_s = –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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673