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Received for publication November 15, 2005.
Revised January 27, 2006.
Accepted for publication January 27, 2006.
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 (Yasui-Furukori et al., 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 Km and Vmax values of 70.2 µM 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 (Shimizu et al., Drug Metab Dispos. 33:1477-81, 2005). The Ki values were determined to be 1.86 and 282 µM, for hOAT3 and hOATP1B3, respectively, with Hill coefficient of 0.76 and 0.64, respectively. The Ki 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 likely explained by an inhibition of the renal uptake of fexofenadine via hOAT3, at least in part.
Key words:
drug interactions, organic anion transport, organic cation transport, renal elimination, renal transport, transporters
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