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ESRD Impairs Nonrenal Clearance of Fexofenadine but not Midazolam

Thomas D. Nolin^*, Reginald F. Frye, Phuong Le, Hooman Sadr, Judith Naud^||, Francois A. Leblond^||, Vincent Pichette^|| and Jonathan Himmelfarb^¶

*Department of Pharmacy and Therapeutics, and Center for Clinical Pharmaceutical Research, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania;
Department of Pharmacotherapy and Translational Research, and Center for Pharmacogenomics, University of Florida College of Pharmacy, Gainesville, Florida;
Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, Maine;
Tidewater Kidney Specialists, Norfolk, Virginia;
^||Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont, and Département de Pharmacologie, Université de Montréal, Montréal, Québec, Canada; and
^¶Kidney Research Institute and Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington

Correspondence: Dr. Thomas D. Nolin, University of Pittsburgh School of Pharmacy, Department of Pharmacy & Therapeutics, 808 Salk Hall, 3501 Terrace Street, Pittsburgh, PA 15261. Phone: 412-624-4683; Fax: 412-624-1850; E-mail: nolin{at}pitt.edu

Received for publication January 21, 2009. Accepted for publication June 24, 2009.

ESRD can affect the pharmacokinetic disposition of drugs subject to nonrenal clearance. Cytochrome P450 (CYP) enzymes, including CYP3A, and multiple intestinal and hepatic drug transporters are thought to mediate this process, but the extent to which kidney disease alters the function of these proteins in humans is unknown. We used midazolam and fexofenadine to assess CYP3A (intestinal and hepatic) and drug transport, respectively, in patients with ESRD and healthy control subjects. We evaluated the effect of uremia on CYP3A and transporter expression in vitro by incubating normal rat hepatocytes and enterocytes with serum drawn from study participants. ESRD dramatically reduced nonrenal transporter function, evidenced by a 63% decrease in clearance (P < 0.001) and a 2.8-fold increase in area under the plasma concentration–time curve for fexofenadine (P = 0.002), compared with control subjects. We did not observe significant differences in midazolam or 1'-hydroxymidazolam clearance or area under the curve after oral administration, suggesting that CYP3A function is not changed by ESRD. Changes in hepatocyte and enterocyte protein expression in the presence of uremic serum were consistent with in vivo results. These findings demonstrate a mechanism for altered drug disposition in kidney disease, which may partially account for the high rates of drug toxicity in this population.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673