Abstract
The membrane transport of many cationic prescription drugs depends on facilitated transport by organic cation transporters of which several members, including OCT2 (SLC22A2), are sensitive to inhibition by select tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs may differentially interact with the renal transporter MATE1 (SLC47A1) and influence the elimination and toxicity of the MATE1 substrate oxaliplatin. Interactions with FDA-approved TKIs were evaluated in transfected HEK293 cells, and in vivo pharmacokinetic studies were performed in wild-type, MATE1-deficient, and OCT2/MATE1-deficient mice. Of 57 TKIs evaluated, 37 potently inhibited MATE1 function by >80% through a non-competitive, reversible, substrate-independent mechanism. The urinary excretion of oxaliplatin was reduced by about 2-fold in mice with a deficiency of MATE1 or both OCT2 and MATE1 (p < 0.05), without impacting markers of acute renal injury. In addition, genetic or pharmacological inhibition of MATE1 did not significantly alter plasma levels of oxaliplatin, suggesting that MATE1 inhibitors are unlikely to influence the safety or drug-drug interaction liability of oxaliplatin-based chemotherapy.
Highlights
Membrane-transporters are key regulators of selective cellular permeability [1], and mediate the passage of many endogenous metabolites such as amino acids and nucleosides as well as small-molecule xenobiotics across the plasma membrane [2]
We evaluated the impact of dasatinib on concentrations of NMN in mice and found that oral administration of the tyrosine kinase inhibitors (TKIs) at a dose of 15 mg/kg resulted in a transient, statistically significant increase in the plasma levels of NMN in wild-type mice to a degree that resembles those observed in MATE1-deficient mice at baseline (Figure 4B)
We identified MATE1 as a transporter that is sensitive to potent inhibition by a remarkably large number of small molecule drugs in the class of TKIs, and demonstrated through functional validation studies using genetic and pharmacological approaches that the observed inhibitory properties are potentially related to an effect on transcription
Summary
Membrane-transporters are key regulators of selective cellular permeability [1], and mediate the passage of many endogenous metabolites such as amino acids and nucleosides as well as small-molecule xenobiotics across the plasma membrane [2]. They are key determinants in normal physiology and pathophysiology, as well as therapeutic response to drugs. Transporter-mediated uptake or efflux can lead to emergence of drug sensitive or resistant phenotypes in target cells [3], and as such affect therapeutic efficacy.
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