Investigation of endogenous compounds for assessing the drug interactions in the urinary excretion involving multidrug and toxin extrusion proteins

Koji Kato, Haruyuki Mori, Tomoko Kito, Miyu Yokochi, Sumito Ito, Katsuhisa Inoue, Atsushi Yonezawa, Toshiya Katsura, Yuji Kumagai, Hiroaki Yuasa, Yoshinori Moriyama, Ken Ichi Inui, Hiroyuki Kusuhara, Yuichi Sugiyama

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Purpose: 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.

Original languageEnglish
Pages (from-to)136-147
Number of pages12
JournalPharmaceutical Research
Volume31
Issue number1
DOIs
Publication statusPublished - Jan 2014

Fingerprint

Drug interactions
Thiamine
Drug Interactions
Carnitine
Extrusion
Pyrimethamine
Urine
Kidney
HEK293 Cells
Proteins
Plasmas
Deuterium compounds
Pharmaceutical Preparations
Plasma (human)
Pharmacokinetics
Metabolomics
Deuterium
Liquid chromatography
Biomarkers
Liquid Chromatography

Keywords

  • drug interaction
  • metabolomics
  • multidrug and toxin extrusion protein
  • organic cation
  • tubular secretion

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Organic Chemistry
  • Molecular Medicine
  • Pharmacology (medical)
  • Biotechnology
  • Pharmacology

Cite this

Investigation of endogenous compounds for assessing the drug interactions in the urinary excretion involving multidrug and toxin extrusion proteins. / Kato, Koji; Mori, Haruyuki; Kito, Tomoko; Yokochi, Miyu; Ito, Sumito; Inoue, Katsuhisa; Yonezawa, Atsushi; Katsura, Toshiya; Kumagai, Yuji; Yuasa, Hiroaki; Moriyama, Yoshinori; Inui, Ken Ichi; Kusuhara, Hiroyuki; Sugiyama, Yuichi.

In: Pharmaceutical Research, Vol. 31, No. 1, 01.2014, p. 136-147.

Research output: Contribution to journalArticle

Kato, K, Mori, H, Kito, T, Yokochi, M, Ito, S, Inoue, K, Yonezawa, A, Katsura, T, Kumagai, Y, Yuasa, H, Moriyama, Y, Inui, KI, Kusuhara, H & Sugiyama, Y 2014, 'Investigation of endogenous compounds for assessing the drug interactions in the urinary excretion involving multidrug and toxin extrusion proteins', Pharmaceutical Research, vol. 31, no. 1, pp. 136-147. https://doi.org/10.1007/s11095-013-1144-y
Kato, Koji ; Mori, Haruyuki ; Kito, Tomoko ; Yokochi, Miyu ; Ito, Sumito ; Inoue, Katsuhisa ; Yonezawa, Atsushi ; Katsura, Toshiya ; Kumagai, Yuji ; Yuasa, Hiroaki ; Moriyama, Yoshinori ; Inui, Ken Ichi ; Kusuhara, Hiroyuki ; Sugiyama, Yuichi. / Investigation of endogenous compounds for assessing the drug interactions in the urinary excretion involving multidrug and toxin extrusion proteins. In: Pharmaceutical Research. 2014 ; Vol. 31, No. 1. pp. 136-147.
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abstract = "Purpose: 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.",
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AU - Ito, Sumito

AU - Inoue, Katsuhisa

AU - Yonezawa, Atsushi

AU - Katsura, Toshiya

AU - Kumagai, Yuji

AU - Yuasa, Hiroaki

AU - Moriyama, Yoshinori

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N2 - Purpose: 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.

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