title: 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.
authors.affiliation: Department of Pharmacy and Therapeutics, and Center for Clinical Pharmaceutical Research, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania 15261, USA. nolin@pitt.edu
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Nolin
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Frye
authors.forename: Phuong
authors.initials: P
authors.lastname: Le
authors.forename: Hooman
authors.initials: H
authors.lastname: Sadr
authors.forename: Judith
authors.initials: J
authors.lastname: Naud
authors.forename: Francois A
authors.initials: FA
authors.lastname: Leblond
authors.forename: Vincent
authors.initials: V
authors.lastname: Pichette
authors.forename: Jonathan
authors.initials: J
authors.lastname: Himmelfarb
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000328:Adult; D000368:Aged; D000818:Animals; D001806:Blood Urea Nitrogen; D051544:Cytochrome P-450 CYP3A / Q000502:physiology; D020895:Enterocytes / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000502:physiology; D011446:Prospective Studies; D051381:Rats; D017207:Rats, Sprague-Dawley; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027361:Organic Anion Transporters; D016593:Terfenadine; C040081:1-hydroxymethylmidazolam; C093230:fexofenadine; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam
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