Competitive Inhibition of the Luminal Efflux by Multidrug and Toxin Extrusions, but Not Basolateral Uptake by Organic Cation Transporter 2, Is the Likely Mechanism Underlying the Pharmacokinetic Drug-Drug Interactions Caused by Cimetidine in the Kidney
Competitive Inhibition of the Luminal Efflux by Multidrug and Toxin Extrusions, but Not Basolateral Uptake by Organic Cation Transporter 2, Is the Likely Mechanism Underlying the Pharmacokinetic Drug-Drug Interactions Caused by Cimetidine in the Kidney
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DOI：
10.1124/jpet.111.184986
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发表时间：
2012-02-01
影响因子：
3.5
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
--
作者：
Ito, Sumito;Kusuhara, Hiroyuki;Sugiyama, Yuichi
用H2受体拮抗剂西咪替丁研究了人肾小管分泌有机阳离子的情况。我们报告了西咪替丁对有机阳离子内流和外流转运蛋白[分别为人有机阳离子转运蛋白1（hOCT 1）和hOCT 2以及人多药和毒素外排蛋白1（hMATE 1）和hMATE 2-K]的抑制效力的系统综合分析。通过使用五种底物[四乙基铵（TEA）、二甲双胍、1-甲基-4-苯基吡啶、4-（4-（二甲氨基）苯乙烯基）-N-甲基吡啶和间碘苄基胍]测定西咪替丁的抑制常数（Ki）。对于hOCT 2，它们为95至146 μ M，基于其临床报告的血浆未结合浓度（3.6 - 7.8 μ M），提供至多10%的抑制。相比之下，西咪替丁是MATE 1和MATE 2-K的强效抑制剂，Ki值（μ M）分别为1.1 - 3.8和2.1 - 6.9。对于小鼠Oct 1（mOct 1）、mOct 2和小鼠Mate 1观察到相同的趋势。20 μ M西咪替丁对小鼠肾切片摄取二甲双胍的影响可忽略不计。通过恒定输注给予小鼠西咪替丁，使血浆未结合浓度达到21.6 μ M，以检查其对体内Mate 1探针（二甲双胍、TEA和头孢氨苄）肾脏处置的影响。西咪替丁使二甲双胍的肾脏和肝脏血浆比均增加了2.4倍，而肾脏清除率没有改变。与对照组相比，西咪替丁还使TEA和头孢氨苄的肾-血浆比增加了8.0倍和3.3倍，并使肾清除率分别从49 ml/min/kg降至23 ml/min/kg和11 ml/ min/ kg降至6.6 ml/ min/ kg。这些结果表明，MATE（而非OCT 2）的抑制可能是与西咪替丁在肾脏消除中发生药物间相互作用的机制。
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.