Effects of Dose and Route on the Disposition and Kinetics of 1-Butyl-1-methylpyrrolidinium Chloride in Male F-344 Rats

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 [C-14]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 [C-14]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 [C-14]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 [C-14]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 [C-14]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 mu M) and inhibitor of (IC50/tetraethylammonium = 0.5 mu M) 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.