title: Effects of dose and route on the disposition and kinetics of 1-butyl-1-methylpyrrolidinium chloride in male F-344 rats.
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 [(14)C]BmPy-Cl (50 mg/kg), BmPy-Cl in the blood decreased rapidly after C(max) of 89.1 min with a distribution half-life (t(1/2)(alpha)) of 21 min, an elimination half-life (t(1/2)(beta)) 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 [(14)C]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 [(14)C]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 [(14)C]BmPy-Cl (5 mg/kg) was moderate when it was applied in dimethylformamide-water (34 + or - 13%), variable in water (22 + or - 8%), or minimal in ethanol-water (13 + or - 1%) vehicles. Urine was the predominant route of elimination regardless of vehicle. Only parent [(14)C]BmPy-Cl was detected in the urine after all doses and routes of administration. BmPy-Cl was found to be a substrate for (K(t) = 37 microM) and inhibitor of (IC(50/tetraethylammonium) = 0.5 microM) 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.
authors.affiliation: Department of Pharmacology, College of Medicine, the University of Arizona, Tucson, Arizona, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Knudsen
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.forename: R K
authors.initials: RK
authors.lastname: Kuester
authors.forename: M J
authors.initials: MJ
authors.lastname: Hooth
authors.forename: I G
authors.initials: IG
authors.lastname: Sipes
mesh_terms: D000818:Animals; D016466:CHO Cells; D002712:Chlorides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006224:Cricetinae; D003412:Cricetulus; D004333:Drug Administration Routes; D006801:Humans; D008297:Male; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D002712:Chlorides; D011759:Pyrrolidines
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