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ESRD impairs nonrenal clearance of fexofenadine but not midazolam.

Abstract
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.
AuthorsThomas D Nolin, Reginald F Frye, Phuong Le, Hooman Sadr, Judith Naud, Francois A Leblond, Vincent Pichette, Jonathan Himmelfarb
JournalJournal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 20 Issue 10 Pg. 2269-76 (Oct 2009) ISSN: 1533-3450 [Electronic] United States
PMID19696225 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Organic Anion Transporters
  • P-Glycoprotein
  • 1-hydroxymethylmidazolam
  • Terfenadine
  • fexofenadine
  • Cytochrome P-450 CYP3A
  • Midazolam
Topics
  • Adult
  • Aged
  • Animals
  • Blood Urea Nitrogen
  • Cytochrome P-450 CYP3A (physiology)
  • Enterocytes (metabolism)
  • Female
  • Hepatocytes (metabolism)
  • Humans
  • Kidney Failure, Chronic (metabolism)
  • Male
  • Metabolic Clearance Rate
  • Midazolam (analogs & derivatives, pharmacokinetics)
  • Middle Aged
  • Organic Anion Transporters (physiology)
  • P-Glycoprotein (physiology)
  • Prospective Studies
  • Rats
  • Rats, Sprague-Dawley
  • Terfenadine (analogs & derivatives, pharmacokinetics)

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