Probenecid, but not cystic fibrosis, alters the total and renal clearance of fexofenadine.
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.
Department of Pharmacy, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Shanshan
S
Liu
Paul M
PM
Beringer
Levita
L
Hidayat
Adupa P
AP
Rao
Stan
S
Louie
Gilbert J
GJ
Burckart
Bertrand
B
Shapiro
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D007483:Iothalamic Acid / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology*; D011446:Prospective Studies; D012076:Renal Agents / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000378:metabolism; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006634:Histamine H1 Antagonists; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D012076:Renal Agents; C114338:organic anion transport protein 3; D007483:Iothalamic Acid; D016593:Terfenadine; D004247:DNA; C093230:fexofenadine; D011339:Probenecid