Abstract
Studies were conducted to characterize the effects of dose and route of administration on the disposition of 1-butyl-1-methylpyrrolidinium (BmPy-Cl) in male Fischer-344 rats. After a single oral administration of [14C]BmPy-Cl (50 mg/kg), BmPy-Cl in the blood decreased rapidly after Cmax of 89.1 min with a distribution half-life (t1/2α) of 21 min, an elimination half-life (t1/2β) of 5.6 h, and a total body clearance of 7.6 ml/min. After oral administration (50, 5, and 0.5 mg/kg), 50 to 70% of the administered radioactivity was recovered in the feces, with the remainder recovered in the urine. Serial daily oral administrations of [14C]BmPy-Cl (50 mg/kg/day for 5 days) did not result in a notable alteration in disposition or elimination. After each administration, 88 to 94% of the dose was eliminated in a 24-h period, with 63 to 76% of dose recovered in the feces. Intravenous administration of [14C]BmPy-Cl (5 mg/kg) resulted in biphasic elimination. Oral systemic bioavailability was 43.4%, approximately equal to the dose recovered in urine after oral administration (29–38%). Total dermal absorption of [14C]BmPy-Cl (5 mg/kg) was moderate when it was applied in dimethylformamide-water (34 ± 13%), variable in water (22 ± 8%), or minimal in ethanol-water (13 ± 1%) vehicles. Urine was the predominant route of elimination regardless of vehicle. Only parent [14C]BmPy-Cl was detected in the urine after all doses and routes of administration. BmPy-Cl was found to be a substrate for (Kt = 37 μM) and inhibitor of (IC50/tetraethylammonium = 0.5 μM) human organic cation transporter 2. In summary, BmPy-Cl is moderately absorbed, extracted by the kidney, and eliminated in the urine as parent compound, independent of dose, number, or route of administration.
- BmPy-Cl, 1-butyl-1-methylpyrrolidinium chloride
- IL, ionic liquid
- Bmim-Cl, 1-butyl-3-methylimidazolium chloride
- NBuPy-Cl, N-butylpyridinium chloride
- TEA, tetraethylammonium trifluoroacetate
- DMF, dimethylformamide
- HPLC, high-pressure liquid chromatography
- JVC, jugular vein cannula
- OCT, organic cation transporter
- h, human
- CHO, Chinese hamster ovary
- Kt, concentration of substrate that results in half maximal transport
- EtOH, ethanol
- Cmax, maximum concentration of 14C radioactivity in blood.
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, Intramural Research Program, Research Project Number 1 [Grant Z01-ES045004-11 BB]; 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.
doi:10.1124/dmd.109.029082
- Received June 18, 2009.
- Accepted August 17, 2009.
- Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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