Inhibition of oat3-mediated renal uptake as a mechanism for drug-drug interaction between fexofenadine and probenecid.
Fexofenadine, a nonsedating antihistamine drug, is effective for the treatment of seasonal allergic rhinitis and chronic urticaria. Simultaneous administration of probenecid increases the plasma concentration of fexofenadine due to an inhibition of its renal elimination in healthy volunteers (Clin Pharmacol Ther 77:17-23, 2005). The purpose of the present study is to investigate the possibility that the drug-drug interaction between fexofenadine and probenecid involves the renal basolateral uptake process. The uptake of fexofenadine was determined in HEK293 cells expressing human organic anion transporter 1 (OAT1/SLC22A6), OAT2 (SLC22A7), OAT3 (SLC22A8), and organic cation transporter 2 (OCT2/SLC22A2). Only hOAT3-HEK showed a significantly greater accumulation of fexofenadine than that in vector-HEK, which was saturable with K(m) and V(max) values of 70.2 microM and 120 pmol/min/mg protein, respectively. Inhibition potency of probenecid for the uptake of fexofenadine was compared between hOAT3 and organic anion-transporting peptide 1B3 (hOATP1B3), a transporter responsible for the hepatic uptake of fexofenadine (Drug Metab Dispos 33:1477-1481, 2005). The K(i) values were determined to be 1.30 and 130 microM for hOAT3 and hOATP1B3, respectively, with Hill coefficients of 0.76 and 0.64, respectively. The K(i) value of probenecid for hOAT3, but not for hOATP1B3, was significantly lower than the maximum unbound plasma concentration of probenecid at clinical dosages. These results suggest that the renal drug-drug interaction between fexofenadine and probenecid is probably explained by an inhibition of the renal uptake of fexofenadine via hOAT3, at least in part.
Tahara
Harunobu
H
Graduate School of Pharmaceutical Sciences University of Tokyo Hongo, Tokyo, 113-0033, Japan.
Kusuhara
Hiroyuki
H
Maeda
Kazuya
K
Koepsell
Hermann
H
Fuse
Eiichi
E
Sugiyama
Yuichi
Y
D018926:Anti-Allergic Agents / Q000378:metabolism*; D001693:Biological Transport, Active; D002853:Chromatography, Liquid; D004347:Drug Interactions; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D013058:Mass Spectrometry; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D011339:Probenecid / Q000494:pharmacology*; D012076:Renal Agents / Q000494:pharmacology*; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000378:metabolism
D018926:Anti-Allergic Agents; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D012076:Renal Agents; C491013:SLC22A2 protein, human; C490280:SLC22A7 protein, human; C114338:organic anion transport protein 3; D016593:Terfenadine; C093230:fexofenadine; D011339:Probenecid