Abstract
Studies were conducted to characterize the effect of dose and route of administration on the disposition of N-butylpyridinium chloride (NBuPy-Cl), an ionic liquid with solvent properties. Urine was the major route of NBuPy-Cl excretion after intravenous (5 mg/kg), single oral (0.5, 5, or 50 mg/kg), or repeated oral (50 mg/kg/day, 5 days) administration to male F-344 rats and single oral (50 mg/kg) administration to female B6C3F1 mice. Depending on the vehicle, absorption after dermal application (5 mg/kg, 125 μg/cm2) was 10 to 35% at 96 h. After the single intravenous dose, the blood concentration of NBuPy-Cl decreased in a biphasic manner with an elimination half-life of 2.2 h and a clearance of 7 ml/min. After single oral administration of NBuPy-Cl (50 mg/kg), maximum blood concentration was reached at 1.3 h, and the bioavailability was determined to be 47% at 6 h based on the blood toxicokinetics and 67% at 72 h based on urinary excretion. In all the urine and blood samples, only the parent compound was detected. Coadministration of NBuPy-Cl and inulin (by intravenous injection) revealed that the clearance of NBuPy-Cl exceeded the rat glomerular filtration rate. After incubation with Chinese hamster ovary cells expressing human organic cation transporter 2 (hOCT2), NBuPy-Cl was transported effectively (Kt = 18 μM), and also a potent inhibitor of hOCT2 mediated tetraethylammonium transport (IC50 = 2.3 μM). In summary, NBuPy-Cl is partially absorbed from the gastrointestinal tract and eliminated rapidly in the urine as parent compound most likely by renal glomerular filtration and OCT2-mediated secretion.
Footnotes
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This work was supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grants N01-ES45529, ES06694]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant ZO1-ES045004-11 BB] (Intramural Research Program, Research Project Number 1); and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK58251].
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.022681.
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ABBREVIATIONS: NBuPy-Cl, N-butylpyridinium chloride; IL, ionic liquid; Bmim-Cl, 1-butyl-3-methylimidazolium chloride; OCT, organic cation transporter; TEA, tetraethylammonium trifluoroacetate; DMF, dimethylformamide; JVC, jugular vein cannula; LSC, liquid scintillation counter; HPLC, high-pressure liquid chromatography; hOCT2, human organic cation transporter 2; CHO, Chinese hamster ovary; WB, Waymouth's buffer; Kt, concentration of substrate that results in half-maximal transport; t1/2α, distribution half-life; Vss, volume of distribution at steady state; t1/2β, elimination half-life; AUC, area under the curve.
- Received July 18, 2008.
- Accepted January 21, 2009.
- U.S. Government work not protected by U.S. copyright.
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