TY - JOUR
T1 - Involvement of Organic Cation Transporters in the Kinetics of Trimethylamine N-oxide
AU - Miyake, Takeshi
AU - Mizuno, Tadahaya
AU - Mochizuki, Tatsuki
AU - Kimura, Miyuki
AU - Matsuki, Shunji
AU - Irie, Shin
AU - Ieiri, Ichiro
AU - Maeda, Kazuya
AU - Kusuhara, Hiroyuki
N1 - Funding Information:
The study was supported partly through a grant of Long-range Research Initiative (LRI) by Japan Chemical Industry Association (JCIA) (grant no. 13_PT03-01-3 ). Appendix
Publisher Copyright:
© 2017 American Pharmacists Association®
PY - 2017/9
Y1 - 2017/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.xphs.2017.04.067
DO - 10.1016/j.xphs.2017.04.067
M3 - Article
C2 - 28479364
AN - SCOPUS:85022061585
SN - 0022-3549
VL - 106
SP - 2542
EP - 2550
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 9
ER -
