title: Investigation of endogenous compounds for assessing the drug interactions in the urinary excretion involving multidrug and toxin extrusion proteins.
abstract: OBJECTIVE
  Multidrug and toxin extrusion proteins (MATEs) are multispecific organic cation transporters mediating the efflux of various cationic drugs into the urine. The present study aimed at identifying endogenous compounds in human plasma and urine specimens as biomarkers to evaluate drug interactions involving MATEs in the kidney without administration of their exogenous probe drugs.
  
  
  METHODS
  An untargeted metabolomic analysis was performed using urine and plasma samples from healthy volunteers and mice treated with or without the potent MATE inhibitor, pyrimethamine. Plasma and urinary concentrations of candidate markers were measured using liquid chromatography-mass spectrometry. Transport activities were determined in MATE- or OCT2-expressing HEK293 cells. The deuterium-labeled compounds of candidates were administered to mice for pharmacokinetics study.
  
  
  RESULTS
  Urinary excretion of eleven compounds including thiamine and carnitine was significantly lower in the pyrimethamine-treatment group in humans and mice, whereas no endogenous compound was noticeably accumulated in the plasma. The renal clearance of thiamine and carnitine was decreased by 70%-84% and 90%-94% (p < 0.05), respectively, in human. The specific uptake of thiamine was observed in MATE1-, MATE2-K- or OCT2-expressing HEK293 cells with Km of 3.5 ± 1.0, 3.9 ± 0.8 and 59.9 ± 6.7 μM, respectively. The renal clearance of carnitine-d 3 was decreased by 62% in mice treated with pyrimethamine.
  
  
  CONCLUSIONS
  Our findings indicate that MATEs account for the efflux of thiamine and perhaps carnitine as well as drugs into the urine. The urinary excretion of thiamine is useful to detect drug interaction involving MATEs in the kidney.
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kato
authors.forename: Haruyuki
authors.initials: H
authors.lastname: Mori
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kito
authors.forename: Miyu
authors.initials: M
authors.lastname: Yokochi
authors.forename: Sumito
authors.initials: S
authors.lastname: Ito
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Inoue
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yonezawa
authors.forename: Toshiya
authors.initials: T
authors.lastname: Katsura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yuasa
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Moriyama
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000328:Adult; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D015415:Biomarkers / Q000097:blood* / Q000652:urine*; D002460:Cell Line; D004347:Drug Interactions / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D027701:Organic Cation Transport Proteins
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