Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney.

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Kito T, Ito S, Mizuno T, Maeda K, Kusuhara H

Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney.

Drug Metab Pharmacokinet. 2019 Feb;34(1):87-94. doi: 10.1016/j.dmpk.2018.08.005. Epub 2018 Sep 20.

PubMed ID

30528339 [ View in PubMed

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Abstract

The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with Ki values (muM) of 0.030-0.28 and 2.4-5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with Km values of 2.3 +/- 0.9 and 0.018 +/- 0.004 muM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CLR) of trimethoprim (mL/min/kg) from 40.0 +/- 5.1 to 20.1 +/- 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CLR (mL/min/kg) of trimethoprim decreased to 25.9 +/- 3.2, 13.5 +/- 5.7, and 8.92 +/- 1.50 at the respective rates. Trimethoprim decreased the CLR of rhodamine 123 in an infusion rate-dependent manner: 11.5 +/- 1.3 (control), 5.17 +/- 1.55, 1.31 +/- 0.50, and 0.532 +/- 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates.

DrugBank Data that Cites this Article

Drugs

Trimethoprim

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Trimethoprim	Multidrug and toxin extrusion protein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Trimethoprim	Multidrug and toxin extrusion protein 2	Protein	Humans	Unknown	Substrate Inhibitor	Details