Abstract
Cimetidine is known to cause drug-drug interactions (DDIs) with organic cations in the kidney, and a previous clinical study showed that coadministration of cimetidine or probenecid with fexofenadine (FEX) decreased its renal clearance. FEX was taken up into human kidney by human organic anion transporter (hOAT) 3 (SLC22A8), but the mechanism of its luminal efflux has not been clarified. The present study examined the molecular mechanism of these DDIs. Saturable uptake of FEX was observed in human kidney slices, with Km and Vmax values of 157 ± 7 μM and 418 ± 16 nmol/15 min/g kidney, respectively. Cimetidine only slightly inhibited its uptake even at 100 μM, far greater than its clinically relevant concentration, whereas 10 μM probenecid markedly inhibited its uptake. As candidate transporters for the luminal efflux of FEX, we focused on human multidrug and toxin extrusions MATE1 (SLC47A1) and MATE2-K (SLC47A2). Saturable uptake of FEX could be observed in human embryonic kidney 293 cells expressing human MATE1 (hMATE1), whereas hMATE2-K-specific uptake of FEX was too small to conduct its further kinetic analysis. The hMATE1-mediated uptake clearance of FEX was inhibited by cimetidine in a concentration-dependent manner, and it was decreased to 60% of the control value in the presence of 3 μM cimetidine. Taken together, our results suggest that the DDI of FEX with probenecid can be explained by the inhibition of renal uptake mediated by hOAT3, whereas the DDI with cimetidine is mainly caused by the inhibition of hMATE1-mediated efflux of FEX rather than the inhibition of its renal uptake process.
Footnotes
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This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology grant-in-aid for Scientific Research (A) [Grant 20249008] and grant-in-aid for Young Scientists (B) [Grant 19790119].
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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.108.023911.
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ABBREVIATIONS: DDI, drug-drug interaction; FEX, fexofenadine; OAT, organic anion transporter; OCT, organic cation transporter; h, human; MATE, multidrug and toxin extrusion; TEA, tetraethylammonium; r, rat; m, mouse; HEK, human embryonic kidney; PAH, p-aminohippurate; DMEM, Dulbecco's modified Eagle's medium; PCR, polymerase chain reaction; LC/MS, liquid chromatography/mass spectrometry; PCG, benzylpenicillin; MDR, multidrug resistance; MRP, multidrug resistance-associated protein.
- Received August 13, 2008.
- Accepted December 8, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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