Involvement of Organic Cation Transporters in the Kinetics of Trimethylamine N-oxide

Takeshi Miyake, Tadahaya Mizuno, Tatsuki Mochizuki, Miyuki Kimura, Shunji Matsuki, Shin Irie, Ichiro Ieiri, Kazuya Maeda, Hiroyuki Kusuhara

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Abstract

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.

Original languageEnglish
Pages (from-to)2542-2550
Number of pages9
JournalJournal of Pharmaceutical Sciences
Volume106
Issue number9
DOIs
Publication statusPublished - Sep 2017

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All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Miyake, T., Mizuno, T., Mochizuki, T., Kimura, M., Matsuki, S., Irie, S., ... Kusuhara, H. (2017). Involvement of Organic Cation Transporters in the Kinetics of Trimethylamine N-oxide. Journal of Pharmaceutical Sciences, 106(9), 2542-2550. https://doi.org/10.1016/j.xphs.2017.04.067