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.
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- 30528339 [ View in PubMed]
- 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
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Trimethoprim Multidrug and toxin extrusion protein 1 Protein Humans UnknownSubstrateInhibitorDetails Trimethoprim Multidrug and toxin extrusion protein 2 Protein Humans UnknownSubstrateInhibitorDetails