Characterization of the inhibitory effects of N-butylpyridinium chloride and structurally related ionic liquids on organic cation transporters 1/2 and human toxic extrusion transporters 1/2-K in vitro and in vivo

Yaofeng Cheng, Lucy J. Martinez-Guerrero, Stephen Wright, Robert K. Kuester, Michelle J. Hooth, I. Glenn Sipes

Research output: Contribution to journalArticle

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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 the 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 cation transporters (OCTs) and multidrug and toxic extrusion transporters (MATEs) in vitro and in vivo. After Chinese hamster ovary cells expressing rat (r) OCT1, rOCT2, human (h) OCT2, 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 per hour) was also infused into rats to assess its effect on the pharmacokinetics of metformin, a substrate of OCTs and MATEs. NBuPy-Cl, Bmim-Cl, and BmPy-Cl displayed strong inhibitory effects on these transporters (IC 50 = 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 IC 50 values were 0.1, 3.8, 14, and 671 μM (hexyl-, butyl-, and 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 coadministration 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.

Original languageEnglish (US)
Pages (from-to)1755-1761
Number of pages7
JournalDrug Metabolism and Disposition
Volume39
Issue number9
DOIs
StatePublished - Sep 2011

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Organic Cation Transporter 1
Ionic Liquids
Poisons
Chlorides
Cations
Metformin
Pharmacokinetics
Methyl Chloride
Kidney
Cricetulus
In Vitro Techniques
Ovary
Salts
Urine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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Characterization of the inhibitory effects of N-butylpyridinium chloride and structurally related ionic liquids on organic cation transporters 1/2 and human toxic extrusion transporters 1/2-K in vitro and in vivo. / Cheng, Yaofeng; Martinez-Guerrero, Lucy J.; Wright, Stephen; Kuester, Robert K.; Hooth, Michelle J.; Sipes, I. Glenn.

In: Drug Metabolism and Disposition, Vol. 39, No. 9, 09.2011, p. 1755-1761.

Research output: Contribution to journalArticle

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