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 [(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.
Knudsen
G A
GA
Department of Pharmacology, College of Medicine, the University of Arizona, Tucson, Arizona, USA.
Cheng
Y
Y
Kuester
R K
RK
Hooth
M J
MJ
Sipes
I G
IG
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
D002712:Chlorides; D011759:Pyrrolidines
Environ Health Perspect. 2007 Oct;115(10):1448-53
17938734
Ecotoxicol Environ Saf. 2007 Jul;67(3):430-8
17034854
Pharmacogenomics. 2008 May;9(5):597-624
18466105
J Pharm Biomed Anal. 2005 Sep 1;39(1-2):233-45
15899570
Toxicology. 2007 Jul 31;237(1-3):158-167
17582672
J Pharmacol Exp Ther. 2004 Jan;308(1):2-9
14576340
Drug Metab Dispos. 2009 Feb;37(2):408-16
19029203
Toxicol Sci. 2005 May;85(1):476-90
15716482
Environ Toxicol. 2009 Aug;24(4):388-95
18825729
Food Chem Toxicol. 1993 Sep;31(9):615-21
8406237
J Biol Chem. 1998 Nov 20;273(47):30915-20
9812985
Drug Metab Dispos. 2008 Feb;36(2):284-93
17967929
Environ Health Perspect. 1998 Feb;106 Suppl 1:253-71
9539018
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):4814-9
17360370
J Membr Biol. 1991 Jun;122(2):127-41
1895338
Mol Pharmacol. 2005 Apr;67(4):1067-77
15630081
J Phys Chem B. 2008 Oct 23;112(42):13335-43
18826270
Toxicol Sci. 2007 Apr;96(2):237-45
17234645
Environ Toxicol Chem. 2005 Jan;24(1):87-92
15683171
Environ Toxicol Chem. 2005 Jul;24(7):1759-65
16050594
Drug Metab Dispos. 2009 Apr;37(4):909-16
19171679
Chem Rev. 1999 Aug 11;99(8):2071-2084
11849019