Importance of the multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics

Yonezawa, Atsushi; Inui, Ken Ichi

doi:10.1111/j.1476-5381.2011.01394.x

Cited by 171 publications

(119 citation statements)

References 65 publications

(110 reference statements)

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“…As noted earlier, metformin is cleared in the kidney by both filtration in the glomerulus and tubular secretion. 51,52 . Surprisingly, in a recent study of the effect of the H2-receptor antagonist, famotidine on metformin pharmacokinetics, there was some evidence that the renal clearance of metformin increased after famotidine 53 , consistent with the drug inhibiting a re-absorptive transporter for metformin in the kidney.…”

Section: Transporters Involved In Metformin Renal Eliminationmentioning

confidence: 99%

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

Liang

Giacomini

2017

Journal of Pharmaceutical Sciences

128

113

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Metformin, widely used as first-line treatment for type 2 diabetes, exists primarily as a hydrophilic cation at physiological pHs. As such, membrane transporters play a substantial role in its absorption, tissues distribution, and renal elimination. Multiple organic cation transporters are determinants of the pharmacokinetics of metformin, and many of them are important in its pharmacological action, as mediators of metformin entry into target tissues. Further, a recent genomewide association study (GWAS) in a large multi-ethnic population implicated polymorphisms in SLC2A2, encoding the glucose transporter, GLUT2, as important determinants of response to metformin. Here, we describe the key transporters associated with metformin pharmacokinetics and response.

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Section: Transporters Involved In Metformin Renal Eliminationmentioning

confidence: 99%

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

Liang

Giacomini

2017

Journal of Pharmaceutical Sciences

128

113

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“…MATE1 is highly expressed in the kidney, liver, adrenal gland, skeletal muscle, and several other tissues, whereas MATE2K is specifically expressed in the kidney (Masuda et al, 2006). Both MATE1 and MATE2K play a role in the renal tubular secretion of cationic drugs and endogenous compounds in humans (Yonezawa and Inui, 2011). OCTN1 and OCTN2 are organic cation transporters expressed in many tissues.…”

Section: Transporters Involved In Creatinine Efflux In the Kidneymentioning

confidence: 99%

The Complexities of Interpreting Reversible Elevated Serum Creatinine Levels in Drug Development: Does a Correlation with Inhibition of Renal Transporters Exist?

Chu

Bleasby

Chan

et al. 2016

Drug Metabolism and Disposition

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In humans, creatinine is formed by a multistep process in liver and muscle and eliminated via the kidney by a combination of glomerular filtration and active transport. Based on current evidence, creatinine can be taken up into renal proximal tubule cells by the basolaterally localized organic cation transporter 2 (OCT2) and the organic anion transporter 2, and effluxed into the urine by the apically localized multidrug and toxin extrusion protein 1 (MATE1) and MATE2K. Druginduced elevation of serum creatinine (SCr) and/or reduced creatinine renal clearance is routinely used as a marker for acute kidney injury. Interpretation of elevated SCr can be complex, because such increases can be reversible and explained by inhibition of renal transporters involved in active secretion of creatinine or other secondary factors, such as diet and disease state. Distinction between these possibilities is important from a drug development perspective, as increases in SCr can result in the termination of otherwise efficacious drug candidates. In this review, we discuss the challenges associated with using creatinine as a marker for kidney damage. Furthermore, to evaluate whether reversible changes in SCr can be predicted prospectively based on in vitro transporter inhibition data, an in-depth in vitro-in vivo correlation (IVIVC) analysis was conducted for 16 drugs with in-house and literature in vitro transporter inhibition data for OCT2, MATE1, and MATE2K, as well as total and unbound maximum plasma concentration (C max and C max,u ) data measured in the clinic.

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“…Unlike mice, however, genotype-phenotype associations in humans are more complex because of the expression of two forms of MATE {MATE1 [Solute carrier family 47A1 (SLC47A1)] and MATE2K (SLC47A2)} (Yonezawa and Inui, 2011). Therefore, although a number of nonsynonymous singlenucleotide polymorphisms have been identified for MATE1, Iwata et al (2012) determined that a single point mutation (rs2289669 G.A) had no effect on either cisplatin plasma concentrations or toxicity.…”

Section: Introductionmentioning

confidence: 99%

Assessment of Vandetanib as an Inhibitor of Various Human Renal Transporters: Inhibition of Multidrug and Toxin Extrusion as a Possible Mechanism Leading to Decreased Cisplatin and Creatinine Clearance

et al. 2013

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Vandetanib was evaluated as an inhibitor of human organic anion transporter 1 (OAT1), OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion (MATE1 and MATE2K) transfected (individually) into human embryonic kidney 293 cells (HEK293). Although no inhibition of OAT1 and OAT3 was observed, inhibition of OCT2-mediated uptake of 1-methyl-4-phenylpyridinium (MPP + ) and metformin was evident (IC 50 of 73.4 6 14.8 and 8.8 61.9 mM, respectively).

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Importance of the multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics

Cited by 171 publications

References 65 publications

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

The Complexities of Interpreting Reversible Elevated Serum Creatinine Levels in Drug Development: Does a Correlation with Inhibition of Renal Transporters Exist?

Assessment of Vandetanib as an Inhibitor of Various Human Renal Transporters: Inhibition of Multidrug and Toxin Extrusion as a Possible Mechanism Leading to Decreased Cisplatin and Creatinine Clearance

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