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.
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 microg/cm(2)) 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 microM), and also a potent inhibitor of hOCT2 mediated tetraethylammonium transport (IC(50) = 2.3 microM). 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.
Cheng
Y
Y
Department of Pharmacology, College of Medicine, The University of Arizona, P.O. Box 245050, Tucson, AZ 85724-5050, USA.
Wright
S H
SH
Hooth
M J
MJ
Sipes
I G
IG
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D008297:Male; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000502:physiology*; D000075102:Organic Cation Transporter 2; D011726:Pyridinium Compounds / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D011726:Pyridinium Compounds; C491012:Slc22a2 protein, mouse; C100590:Slc22a2 protein, rat; C046365:n-butylpyridinium