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Research ArticleArticle

Characterization of the inhibitory effects of N-butylpyridinium chloride and structurally related ionic liquids on OCT1/2 and hMATE1/2-K in vitro and in vivo

Yaofeng Cheng, Lucy J. Martinez-Guerrero, Stephen H. Wright, Michelle J. Hooth and I. Glenn Sipes
Drug Metabolism and Disposition June 6, 2011, dmd.110.035865; DOI: https://doi.org/10.1124/dmd.110.035865
Yaofeng Cheng
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Lucy J. Martinez-Guerrero
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Stephen H. Wright
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Michelle J. Hooth
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I. Glenn Sipes
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  • For correspondence: sipes@email.arizona.edu
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Abstract

Ionic liquids (ILs) are a class of salts that are expected to be used as a new source of solvents and for many other applications. Our previous studies revealed that selected ILs, structurally related organic cations, are eliminated exclusively in urine as parent compound, partially mediated by renal transporters. This study investigated the inhibitory effects of N-butylpyridinium chloride (NBuPy-Cl) and structurally related ILs on organic cations transporters (OCTs) and multidrug and toxic extrusion transporters (MATEs) in vitro and in vivo. After CHO cells expressing rOCT1, rOCT2, hOCT2, hMATE1 or hMATE2-K were constructed, the ability of NBuPy-Cl, 1-methyl-3-butylimidazolium chloride (Bmim-Cl), N-butyl-N-methylpyrrolidinium chloride (BmPy-Cl) and alkyl substituted pyridinium ILs to inhibit these transporters was determined in vitro. NBuPy-Cl (0, 0.5, or 2 mg/kg/h) was also infused into rats to assess its effect on the pharmacokinetics of metformin, a substrate for OCTs and MATEs. NBuPy-Cl, Bmim-Cl and BmPy-Cl displayed strong inhibitory effects on these transporters (IC50: 0.2~8.5 μM). In addition, the inhibitory effects of alkyl substituted pyridinium ILs on OCTs increased dramatically as the length of the alkyl chain increased. The IC50 values were 0.1, 3.8, 14 and 671 μM (hexyl-, butyl-, ethyl-pyridinium and pyridinium chloride) for rOCT2 mediated metformin transport. Similar structurally related inhibitory kinetics were also observed for rOCT1 and hOCT2. The in vivo co-administration study revealed that NBuPy-Cl reduced the renal clearance of metformin in rats. These results demonstrate that ILs compete with other substrates of OCTs and MATEs, and could alter the in vivo pharmacokinetics of such substrates.

  • inhibition
  • organic cation transport
  • pharmacokinetics
  • renal transport
  • Received August 18, 2010.
  • Accepted June 1, 2011.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (3)
Drug Metabolism and Disposition
Vol. 49, Issue 3
1 Mar 2021
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Research ArticleArticle

Characterization of the inhibitory effects of N-butylpyridinium chloride and structurally related ionic liquids on OCT1/2 and hMATE1/2-K in vitro and in vivo

Yaofeng Cheng, Lucy J. Martinez-Guerrero, Stephen H. Wright, Michelle J. Hooth and I. Glenn Sipes
Drug Metabolism and Disposition June 6, 2011, dmd.110.035865; DOI: https://doi.org/10.1124/dmd.110.035865

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Research ArticleArticle

Characterization of the inhibitory effects of N-butylpyridinium chloride and structurally related ionic liquids on OCT1/2 and hMATE1/2-K in vitro and in vivo

Yaofeng Cheng, Lucy J. Martinez-Guerrero, Stephen H. Wright, Michelle J. Hooth and I. Glenn Sipes
Drug Metabolism and Disposition June 6, 2011, dmd.110.035865; DOI: https://doi.org/10.1124/dmd.110.035865
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