RT Journal Article
SR Electronic
T1 The Inhibition of Human Multidrug and Toxin Extrusion 1 Is Involved in the Drug-Drug Interaction Caused by Cimetidine
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 555
OP 559
DO 10.1124/dmd.108.023911
VO 37
IS 3
A1 Soichiro Matsushima
A1 Kazuya Maeda
A1 Katsuhisa Inoue
A1 Kin-ya Ohta
A1 Hiroaki Yuasa
A1 Tsunenori Kondo
A1 Hideki Nakayama
A1 Shigeru Horita
A1 Hiroyuki Kusuhara
A1 Yuichi Sugiyama
YR 2009
UL http://dmd.aspetjournals.org/content/37/3/555.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics