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0091270008319707v1
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DRUG METABOLISM AND TRANSPORT

Probenecid, but Not Cystic Fibrosis, Alters the Total and Renal Clearance of Fexofenadine

Shanshan Liu, MD, Paul M. Beringer, PharmD, Levita Hidayat, PharmD, Adupa P. Rao, MD, Stan Louie, PharmD, Gilbert J. Burckart, PharmD, FCP and Bertrand Shapiro, MD

From the Department of Pharmacy (Dr Liu, Dr Hidayat, Dr Louie, Dr Burckart) and Department of Medicine, Keck School of Medicine (Dr Rao, Dr Shapiro), University of Southern California, Los Angeles. Results were presented at the 21st North American Cystic Fibrosis Conference on October 3-6, 2007.

This study aims to evaluate renal P-glycoprotein (P-gp) activity in patients with cystic fibrosis. P-gp efflux activity in peripheral T cells was measured by flow cytometry in 10 cystic fibrosis and 15 healthy volunteers. Eight cystic fibrosis patients and 8 healthy volunteers were recruited into a crossover pharmacokinetic study in which participants received 180 mg fexofenadine with or without 1 g probenecid twice a day. Genotyping was performed for ABCB1 C1236T, G2677T, and C3435T. P-gp efflux activity in peripheral T cells was not significantly different between cystic fibrosis patients and healthy volunteers. No difference in fexofenadine pharmacokinetic parameters was observed between cystic fibrosis patients and healthy volunteers when fexofenadine was administered with or without probenecid. Coadministration of probenecid significantly increased fexofenadine AUC and decreased the cumulative urinary excretion, total body clearance, and renal clearance. ABCB1 3435 C/T carriers showed increased basal P-gp activity in CD4+ and CD8+ T cells, increased R123-induced efflux activity in CD4+ T cell, and decreased fexofenadine AUC. Fexofenadine disposition and P-gp efflux activity in peripheral T cells was similar between cystic fibrosis patients and healthy volunteers. Probenecid administration significantly reduced the total body and renal clearance of fexofenadine. ABCB1 3435 C/T was associated with an elevated efflux activity compared with C/C subjects.

Key Words: P-glycoprotein • cystic fibrosis • fexofenadine • pharmacokinetics • rhodamine 123

Address for reprints: Paul M. Beringer, PharmD, 1985 Zonal Avenue, Los Angeles, CA 90033; e-mail: beringer{at}usc.edu.


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