Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Fukuoka Mirai Hospital Clinical Research Center, Fukuoka 813-0017, Japan.
J Pharm Sci. 2017 Sep;106(9):2542-2550. doi: 10.1016/j.xphs.2017.04.067. Epub 2017 May 4.
Recent studies suggest that trimethylamine N-oxide (TMAO) is associated with the development of chronic kidney disease and heart failure. In this study, we investigated the importance of organic cation transporters (OCTs) in the clearance and tissue distribution of TMAO. The low-affinity and high-capacity transport of TMAO by mouse and human OCT1 and OCT2 was observed. Uptake and efflux of TMAO by the mouse hepatocytes as well as TMAO uptake into mouse kidney slices were significantly decreased by the addition of tetraethylammonium or Oct1/2 double knockout (dKO). Plasma concentrations of endogenous TMAO and TMAO-d9 given by intravenous infusion was 2-fold higher in Oct1/2 dKO than in wild-type mice due to significant decrease in its renal clearance. These results indicate that OCTs have a crucial role in the kinetics of TMAO in mice. In human, however, the OCT2-mediated tubular secretion in the urinary excretion of TMAO was insignificant because the renal clearance of TMAO was similar to that of creatinine in both young and elderly subjects, suggesting the species difference in the urinary excretion mechanisms of TMAO between mouse and human.
最近的研究表明，三甲胺 N-氧化物（TMAO）与慢性肾病和心力衰竭的发展有关。在这项研究中，我们研究了有机阳离子转运体（OCTs）在 TMAO 的清除和组织分布中的重要性。观察到 TMAO 被小鼠和人 OCT1 和 OCT2 以低亲和力和高容量转运。添加四乙基铵或 Oct1/2 双敲除（dKO）可显著降低 TMAO 在小鼠肝细胞中的摄取和外排，以及 TMAO 进入小鼠肾切片的摄取。由于肾脏清除率显著降低，静脉输注给予内源性 TMAO 和 TMAO-d9 的血浆浓度在 Oct1/2 dKO 小鼠中是野生型小鼠的 2 倍。这些结果表明，OCTs 在小鼠 TMAO 的动力学中起着关键作用。然而，在人类中，OCT2 介导的 TMAO 在尿中的肾小管分泌作用并不重要，因为 TMAO 的肾清除率与年轻和老年受试者的肌酐清除率相似，这表明 TMAO 在小鼠和人类之间的尿排泄机制存在种间差异。
