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

Shen, Hong; Yang, Zheng; Zhao, Weiping; Zhang, Yueping; Rodrigues, A. David

doi:10.1124/dmd.113.053215

Cited by 51 publications

(25 citation statements)

References 37 publications

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“…b Plasma unbound fraction of inhibitors (Templeton et al, 2008, Prueksaritanont et al, 2014, Prueksaritanont et al, 2017 and Goodman & Gilman 10th Edition, 2001. c Concentrations required to inhibit OATP1B-mediated transport by 50% using statins and estradiol 17β glucuronide (Yoshida et al, 2012, Shen et al, 2013, Nakakariya et al, 2016, Vermeer et al, 2016.…”

Section: Discussionmentioning

confidence: 99%

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition

et al. 2018

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Section: Discussionmentioning

confidence: 99%

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition

et al. 2018

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“…(Muller et al, 2015) and for OCT2 inhibition by vandetanib (13-fold, N-methyl-4-phenylpyridinium iodide vs. metformin as probes) (Shen et al, 2013) when the studies were conducted in the same laboratory using the same in vitro system. Substratedependent inhibition of OCT2, MATE1, and MATE2K has been systemically evaluated with several prototypic substrates (Belzer et al, 2013;Martinez-Guerrero and Wright, 2013), suggesting that both OCT2 and MATEs have multiple drug binding sites.…”

Section: Inhibition Of Renal Transporters and Elevation Of Scr: An Inmentioning

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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“…The established OAT2-HEK cells, and OCT2-, MATE1-, and MATE2K-HEK cells and mock cells were cultured at 37°C in an atmosphere of 95% air/ 5% CO 2 and subcultured once per week (Han et al, 2010;Shen et al, 2013). OAT2-HEK cells and other HEK cells used in the current study were passaged less than 10 and 30 times, respectively, to retain consistent transporter expression and functional activity.…”

Section: Introductionmentioning

confidence: 99%

“…Plasmid DNA was prepared using standard methods (Qiagen, Valencia, CA), and sequences were confirmed to be identical to the one reported in the National Center for Biotechnology Information database. The stable transfection of HEK cells with OAT2, using Flp-In expression system, was conducted according to a procedure previously described for the preparation of OCT2-, multidrug and toxin extrusion protein (MATE)1-, and MATE2K-transfected cells (Han et al, 2010;Shen et al, 2013). In brief, HEK Flp-In cells were seeded into a six-well plate at a density of 0.1 million cells/cm 2 in Dulbecco's modified Eagle's growth medium supplemented with 10% fetal calf serum, 0.1 mM nonessential amino acids, and 2 mM L-glutamate, and incubated overnight.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Organic Anion Transporter 2 (SLC22A7): A Highly Efficient Transporter for Creatinine and Species-Dependent Renal Tubular Expression

et al. 2015

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The contribution of organic anion transporter OAT2 (SLC22A7) to the renal tubular secretion of creatinine and its exact localization in the kidney are reportedly controversial. In the present investigation, the transport of creatinine was assessed in human embryonic kidney (HEK) cells that stably expressed human OAT2 (OAT2-HEK) and isolated human renal proximal tubule cells (HRPTCs). The tubular localization of OAT2 in human, monkey, and rat kidney was characterized. The overexpression of OAT2 significantly enhanced the uptake of creatinine in OAT2-HEK cells. Under physiologic conditions (creatinine concentrations of 41.2 and 123.5 mM), the initial rate of OAT2-mediated creatinine transport was approximately 11-, 80-, and 80-fold higher than OCT2, multidrug and toxin extrusion protein (MATE)1, and MATE2K, respectively, resulting in approximately 37-, 1850-, and 80-fold increase of the intrinsic transport clearance when normalized to the transporter protein concentrations. Creatinine intracellular uptake and transcellular transport in HRPTCs were decreased in the presence of 50 mM bromosulfophthalein and 100 mM indomethacin, which inhibited OAT2 more potently than other known creatinine transporters, OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2K (IC 50 : 1.3 mM vs. > 100 mM and 2.1 mM vs. > 200 mM for bromosulfophthalein and indomethacin, respectively) Immunohistochemistry analysis showed that OAT2 protein was localized to both basolateral and apical membranes of human and cynomolgus monkey renal proximal tubules, but appeared only on the apical membrane of rat proximal tubules. Collectively, the findings revealed the important role of OAT2 in renal secretion and possible reabsorption of creatinine and suggested a molecular basis for potential species difference in the transporter handling of creatinine.

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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

Cited by 51 publications

References 37 publications

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition

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

Characterization of Organic Anion Transporter 2 (SLC22A7): A Highly Efficient Transporter for Creatinine and Species-Dependent Renal Tubular Expression

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