Investigation of Endogenous Compounds for Assessing the Drug Interactions in the Urinary Excretion Involving Multidrug and Toxin Extrusion Proteins
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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.
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.
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.
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.
KEY WORDSdrug interaction metabolomics multidrug and toxin extrusion protein organic cation tubular secretion
area under the plasma concentration–time curve
brush border membrane
brush border membrane vesicles
total plasma clearance
glomerular filtration rate
liquid chromatography-mass spectrometry
multidrug and toxin extrusion protein
organic cation transporter
urinary excretion amount
ACKNOWLEDGMENTS AND DISCLOSURE
We thank K. Taguchi, N. Hagima, S. Kamigaso, and K. Iwata of the Taisho Pharmaceutical Company for their skilled and expert technical assistance.
The clinical study was conducted as the NEDO MicroDose-PJ, sponsored by the New Energy and Industrial Technology Development Organization (NEDO), Japan. This study was supported by a Grant-in-Aid for Scientific Research (S) [Grant 24229002], for Scientific Research (B) [Grant 23390034] and for Challenging Exploratory Research  from Japan Society for the Promotion of Science, Japan, and Scientific Research on Innovative Areas HD-Physiology [Grant 23136101] from the Ministry of Education, Science, and Culture of Japan. It was also supported by a Grant-in-Aid from The Nakatomi Foundation.
K. Kato and H. Mori are full-time employees of Taisho Pharmaceutical Company. The authors have no conflicts of interest that are directly relevant to this study.
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