RT Journal Article
SR Electronic
T1 Pharmacokinetic-Pharmacodynamic Modeling of Buspirone and Its Metabolite 1-(2-Pyrimidinyl)-piperazine in Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1130
OP 1137
DO 10.1124/jpet.102.036798
VO 303
IS 3
A1 Klaas P. Zuideveld
A1 Jasna Rusiç-Pavletiç
A1 Hugo J. Maas
A1 Lambertus A. Peletier
A1 Piet H. Van der Graaf
A1 Meindert Danhof
YR 2002
UL http://jpet.aspetjournals.org/content/303/3/1130.abstract
AB The objective of this investigation was to compare the in vivo potency and intrinsic activity of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in rats by pharmacokinetic-pharmacodynamic modeling. Following intravenous administration of buspirone (5 or 15 mg/kg in 15 min) or 1-PP (10 mg/kg in 15 min), the time course of the concentrations in blood were determined in conjunction with the effect on body temperature. The pharmacokinetics of buspirone and 1-PP were analyzed based on a two-compartment model with metabolite formation. Differences in the pharmacokinetics of buspirone and 1-PP were observed with values for clearance of 13.1 and 8.2 ml/min and for terminal elimination half-life of 25 and 79 min, respectively. At least 26% of the administered dose of buspirone was converted into 1-PP. Complex hypothermic effects versus time profiles were observed, which were successfully analyzed on the basis of a physiological indirect response model with set-point control. Both buspirone and 1-PP behaved as partial agonists relative to R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) with values of the intrinsic activity of 0.465 and 0.312, respectively. Differences in the potency were observed with values of 17.6 and 304 ng/ml for buspirone and 1-PP, respectively. The results of this analysis show that buspirone and 1-PP behave as partial 5-hydroxytryptamine1A agonists in vivo and that following intravenous administration the amount of 1-PP formed is too small to contribute to the hypothermic effect.