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Characterization of the Disposition and Toxicokinetics of N-Butylpyridinium Chloride in Male F-344 Rats and Female B6C3F1 Mice and Its Transport by Organic Cation Transporter 2

Departments of Pharmacology (Y.C., I.G.S.) and Physiology (S.H.W.), College of Medicine, the University of Arizona, Tucson, Arizona; and National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (M.J.H.)

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 (K_t = 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.

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				G. A. Knudsen, Y. Cheng, R. K. Kuester, M. J. Hooth, and I. G. Sipes Effects of Dose and Route on the Disposition and Kinetics of 1-Butyl-1-methylpyrrolidinium Chloride in Male F-344 Rats Drug Metab. Dispos., November 1, 2009; 37(11): 2171 - 2177. [Abstract] [Full Text] [PDF]