Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 340, Issue 2, Pages 393-403Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.111.184986
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Funding
- Japan Society for the Promotion of Science [20249008, 23390034]
- Health and Labor Sciences Research Grants
- Grants-in-Aid for Scientific Research [20249008, 23390034] Funding Source: KAKEN
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Cimetidine, an H 2 receptor antagonist, has been used to investigate the tubular secretion of organic cations in human kidney. We report a systematic comprehensive analysis of the inhibition potency of cimetidine for the influx and efflux transporters of organic cations [human organic cation transporter 1 (hOCT1) and hOCT2 and human multidrug and toxin extrusion 1 (hMATE1) and hMATE2-K, respectively]. Inhibition constants (K-i) of cimetidine were determined by using five substrates [tetraethylammonium (TEA), metformin, 1-methyl-4-phenylpyridinium, 4-(4-(dimethylamino) styryl)-N-methylpyridinium, and m-iodobenzylguanidine]. They were 95 to 146 mu M for hOCT2, providing at most 10% inhibition based on its clinically reported plasma unbound concentrations (3.6 -7.8 mu M). In contrast, cimetidine is a potent inhibitor of MATE1 and MATE2-K with K-i values (mu M) of 1.1 to 3.8 and 2.1 to 6.9, respectively. The same tendency was observed for mouse Oct1 (mOct1), mOct2, and mouse Mate1. Cimetidine showed a negligible effect on the uptake of metformin by mouse kidney slices at 20 mu M. Cimetidine was administered to mice by a constant infusion to achieve a plasma unbound concentration of 21.6 mu M to examine its effect on the renal disposition of Mate1 probes (metformin, TEA, and cephalexin) in vivo. The kidney-and liver-toplasma ratios of metformin both were increased 2.4-fold by cimetidine, whereas the renal clearance was not changed. Cimetidine also increased the kidney-to-plasma ratio of TEA and cephalexin 8.0-and 3.3-fold compared with a control and decreased the renal clearance from 49 to 23 and 11 to 6.6 ml/ min/ kg, respectively. These results suggest that the inhibition of MATEs, but not OCT2, is a likely mechanism underlying the drug-drug interactions with cimetidine in renal elimination.
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