Abstract
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 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 (Drug Metab Dispos 33:1477–1481, 2005). The Ki values were determined to be 1.30 and 130 μM for hOAT3 and hOATP1B3, respectively, with Hill coefficients 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 probably explained by an inhibition of the renal uptake of fexofenadine via hOAT3, at least in part.
Footnotes
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This work was supported by Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare for the Research on Regulatory Science of Pharmaceuticals and Medical Devices.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.008375.
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ABBREVIATIONS: OAT, organic anion transporter; hOAT, human OAT; OCT, organic cation transporter; hOCT, human OCT; r, rat; hOATP, human organic anion-transporting peptide; AUC, area under the plasma concentration-time curve; HEK, human embryonic kidney; LC-MS, liquid chromatography-mass spectrometry.
- Received November 14, 2005.
- Accepted January 27, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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