Dose-dependent pharmacokinetics of carbamazepine in rats: determination of the formation clearance of carbamazepine-10,11-epoxide.
The dose dependency of carbamazepine pharmacokinetics was characterized in rats, a common test animal for antiepileptic drug efficacy. With a randomized Latin square schedule, 5, 10, and 20 mg/kg doses of carbamazepine were injected intravenously into six Sprague-Dawley rats followed by the administration of a 5 or 10 mg/kg i.v. dose of CBZ-E to each rat. Following administration, the concentrations of CBZ and carbamazepine-10,11-epoxide (CBZ-E) in whole blood were determined by a reverse-phase HPLC assay. Plasma protein binding of both carbamazepine and CBZ-E was linear over the concentration range observed in this study. Carbamazepine concentration-time plots were log-linear, but the slopes were not parallel. Carbamazepine total-body clearances were 15.1 +/- 3.26, 13.4 +/- 5.66, and 10.0 +/- 3.11 ml/min/kg at the 5, 10, and 20 mg/kg doses, respectively (significance of difference between the 5 and the 20 mg/kg dose = 0.06 less than P less than 0.05; Kruskal-Wallis test, Dunn's procedure). However, the formation clearance to CBZ-E did not change, suggesting that metabolism via other pathways was decreased at higher carbamazepine doses.
Remmel
R P
RP
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Sinz
M W
MW
Cloyd
J C
JC
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D008297:Male; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D012044:Regression Analysis
D001798:Blood Proteins; D002220:Carbamazepine; C012227:carbamazepine epoxide