| N-Methylnicotinamide Is an Endogenous Probe for Evaluation of Drug-Drug Interactions Involving Multidrug and Toxin Extrusions (MATE1 and MATE2-K). | |
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MedLine Citation:
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PMID: 23047651 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Multidrug and toxin extrusion 1 (MATE1) and MATE2-K are H(+)/organic cation exchangers mediating the efflux of cationic drugs into the urine. N-methylnicotinamide (NMN) was found to be an endogenous substrate of MATE1 (Michaelis constant (K(m)) 301 ± 18 µmol/l) and MATE2-K (K(m) 422 ± 63 µmol/l) as well as a basolateral influx transporter, organic cation transporter 2 (K(m) 318 ± 29 µmol/l). A potent MATE inhibitor, pyrimethamine, competitively inhibited the uptake by MATE1 and MATE2-K with inhibition constant (K(i)) values of 83 ± 15 and 56 ± 11 nmol/l, respectively. The uptake of NMN by human kidney brush border membrane vesicles with a H(+) gradient was saturable (K(m) 360 ± 55 µmol/l) and completely inhibited by pyrimethamine. The renal clearance of endogenous NMN was 403 ± 61 in healthy male subjects, and it was significantly decreased to 119 ± 16 ml/min/kg by an oral dose of pyrimethamine (50 mg). These results support the utility of NMN as an endogenous in vivo probe for investigating MATE1 and MATE2-K in humans.Clinical Pharmacology & Therapeutics (2012); advance online publication 10 October 2012. doi:10.1038/clpt.2012.138. |
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Authors:
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S Ito; H Kusuhara; Y Kumagai; Y Moriyama; K Inoue; T Kondo; H Nakayama; S Horita; K Tanabe; H Yuasa; Y Sugiyama |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-10-10 |
Journal Detail:
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Title: Clinical pharmacology and therapeutics Volume: - ISSN: 1532-6535 ISO Abbreviation: Clin. Pharmacol. Ther. Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372741 Medline TA: Clin Pharmacol Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. |
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