Involvement of Organic Cation Transporters in the Clearance and Milk Secretion of Thiamine in Mice

Kato, Koji; Moriyama, Chihiro; Ito, Naoki; Zhang, Xuan; Hachiuma, Kenji; Hagima, Naoko; Iwata, Kazuya; Yamaguchi, Junichi; Maeda, Kazuya; Ito, Kousei; Suzuki, Hiroshi; Sugiyama, Yuichi; Kusuhara, Hiroyuki

doi:10.1007/s11095-014-1608-8

Cited by 24 publications

(36 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…17,19 Therefore, in this study, we hypothesized that the reverse may be true. That is, the thiamine specific transporter, THTR-2, may also interact with various xenobiotics and particularly various prescription drugs.…”

Section: Resultsmentioning

confidence: 97%

Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3)

et al. 2015

View full text Add to dashboard Cite

The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH’s, metformin is transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic cation transporter 1, OCT1, the major hepatic uptake transporter for metformin, was also the primary hepatic uptake transporter for thiamine, vitamin B1. In this study, we tested the reverse, i.e., that metformin is a substrate of thiamine transporters (THTR-1, SLC19A2, and THTR-2, SLC19A3). Our study demonstrated that human THTR-2 (hTHTR-2), SLC19A3, which is highly expressed in the small intestine, but not hTHTR-1, transports metformin (Km = 1.15 ± 0.2 mM) and other cationic compounds (MPP+ and famotidine). The uptake mechanism for hTHTR-2 was pH and electrochemical gradient sensitive. Furthermore, metformin as well as other drugs including phenformin, chloroquine, verapamil, famotidine, and amprolium inhibited hTHTR-2 mediated uptake of both thiamine and metformin. Species differences in the substrate specificity of THTR-2 between human and mouse orthologues were observed. Taken together, our data suggest that hTHTR-2 may play a role in the intestinal absorption and tissue distribution of metformin and other organic cations and that the transporter may be a target for drug–drug and drug–nutrient interactions.

show abstract

Section: Resultsmentioning

confidence: 97%

Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3)

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Experiments in Oct1 knockout mice and humanized OCT1 transgenic mice signal a relevant role of OCT1 in hepatic and possibly intestinal uptake of thiamine (Chen et al, 2014). In Oct1/Oct2 double-knockout mice, plasma concentrations of endogenous thiamine were 5.8-fold higher and renal clearance of exogenous thiamine (high-dose infusion to suppress the extensive renal tubular thiamine reabsorption) was lower by 79% in comparison with the wild-type (Kato et al, 2015). In wild-type mice, the MATE inhibitor pyrimethamine reduced urinary excretion of endogenous thiamine by approximately 70% (Kato et al, 2014) and renal clearance of exogenous thiamine (high-dose infusion to suppress thiamine reabsorption) by 58% (Kato et al, 2015).…”

Section: Biomarkers For Function Of Renal Cation Transporters (Orgmentioning

confidence: 99%

“…N 1 -Methylnicotinamide and thiamine have been proposed as in vivo probes for assessment of the activity of renal MATEs and possibly also of OCT2 (Ito et al, 2012a;Kato et al, 2014Kato et al, , 2015Müller et al, 2015). For both compounds, renal clearance has been proposed as a parameter to assess the potential for drug-drug interactions by inhibition of renal tubular organic cation secretion.…”

Section: Biomarkers For Function Of Renal Cation Transporters (Orgmentioning

confidence: 99%

“…In wild-type mice, the MATE inhibitor pyrimethamine reduced urinary excretion of endogenous thiamine by approximately 70% (Kato et al, 2014) and renal clearance of exogenous thiamine (high-dose infusion to suppress thiamine reabsorption) by 58% (Kato et al, 2015). Taken together, mouse data indicate a role of OCT1 in hepatic thiamine uptake, and it appears that OCT1 may also be involved in uptake of thiamine by the intestine and secretion of thiamine into breast milk (Kato et al, 2015), whereas it is suggested that MATEs (Mate1 in mice) and possibly OCT2 (Oct1 and Oct2 in mice) play a role in renal tubular thiamine secretion processes.…”

Section: Biomarkers For Function Of Renal Cation Transporters (Orgmentioning

confidence: 99%

See 1 more Smart Citation

Biomarkers for In Vivo Assessment of Transporter Function

Müller¹,

Sharma²,

König³

et al. 2018

Pharmacol Rev

View full text Add to dashboard Cite

Drug-drug interactions are a major concern not only during clinical practice, but also in drug development. Due to limitations of in vitro-in vivo predictions of transporter-mediated drug-drug interactions, multiple clinical Phase I drug-drug interaction studies may become necessary for a new molecular entity to assess potential drug interaction liabilities. This is a resource-intensive process and exposes study participants, who frequently are healthy volunteers without benefit from study treatment, to the potential risks of a new drug in development. Therefore, there is currently a major interest in new approaches for better prediction of transporter-mediated drug-drug interactions. In particular, researchers in the field attempt to identify endogenous compounds as biomarkers for transporter function, such as hexadecanedioate, tetradecanedioate, coproporphyrins I and III, or glycochenodeoxycholate sulfate for hepatic uptake via organic anion transporting polypeptide 1B or N-methylnicotinamide for multidrug and toxin extrusion protein-mediated renal secretion. We summarize in this review the currently proposed biomarkers and potential limitations of the substances identified to date. Moreover, we suggest criteria based on current experiences, which may be used to assess the suitability of a biomarker for transporter function. Finally, further alternatives and supplemental approaches to classic drug-drug interaction studies are discussed.

show abstract

“…In this way, OCT1 plays a role in hepatic steatosis through modulation of AMPK pathway and acetyl-CoA carboxylase (ACC) activity (Chen et al, 2014). Oct1 might also be involved in secretory transfer of Oct1 substrates, such as acyclovir, thiamin and cimetidine into milk in mice (Ito et al, 2014;Kato et al, 2015).…”

Section: Function Of Oct1mentioning

confidence: 99%

Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation

Hyršová

Smutný

Trejtnar

et al. 2016

Drug Metabolism Reviews

View full text Add to dashboard Cite

The organic cation transporter 1 (OCT1) is the dominant carrier of organic cationic drugs and some positively charged endogenous compounds into hepatocytes. OCT1 has unique expression pattern. It has the highest expression among drug transporters in normal human hepatocytes with large interindividual variability, but it has negligible expression in other tissues or their tumors. Nowadays, it is clear that the regulation of SLC22A1 gene encoding OCT1 transporter is rather complex and that transactivation with hepatocyte nuclear factor 4α (HNF4α) and CCAAT-enhancer-binding protein (C/EBPs) transcription factors as well as epigenetic regulation contribute to its unique hepatocyte-specific expression pattern. Unfortunately, species- and tissue-specific regulation of OCT1 and its orthologs as well as significant down-regulation in most immortalized cell lines hamper the study of SLC22A1 gene regulation. In the current review, we summarize our current understanding of human OCT1 transporter hepatic gene regulation and we propose potential post-transcriptional regulation by predicted miRNAs. We also discuss in detail recent findings on indirect regulation of the transporter via farnesoid X receptor (FXR), glucocorticoid receptor and pregnane X (PXR) receptor, which point out to potential novel mechanisms of xenobiotic-transporting and drug-metabolizing proteins regulation in the human liver as well as to potentially novel drug-drug interaction mechanisms. We also propose that comprehensive understanding of mechanisms of SLC22A1 gene regulation could direct research for other drug transporters and drug-metabolizing enzymes highly expressed in hepatocytes and controlled by HNF4α or other liver-enriched transcription factors.

show abstract

Involvement of Organic Cation Transporters in the Clearance and Milk Secretion of Thiamine in Mice

Abstract: Oct1 is possibly responsible for the plasma clearance of thiamine via tissue uptake and for milk secretion. Oct1/2 and Mate1 are involved in the renal tubular secretion of thiamine.

Cited by 24 publications

References 51 publications

Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3)

Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3)

Biomarkers for In Vivo Assessment of Transporter Function

Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation

Contact Info

Product

Resources

About