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Vol. 303, Issue 3, 1130-1137, December 2002

Pharmacokinetic-Pharmacodynamic Modeling of Buspirone and Its Metabolite 1-(2-Pyrimidinyl)-piperazine in Rats

Klaas P. Zuideveld1 , Jasna Rusiç-Pavletiç2 , Hugo J. Maas, Lambertus A. Peletier, Piet H. Van der Graaf3 and Meindert Danhof

Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratories, Leiden, The Netherlands (K.P.Z., J.R.-P., H.J.M., P.H.V., M.D.); and Mathematical Institute, Leiden University, Niels Bohrweg, Leiden, The Netherlands (L.A.P.)

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.

1 Present address: Pharsight Corporation, Argentum, 2 Queen Caroline St., Hammersmith, W6 9DT London, UK.

2 Present address: Pliva Ïstra ivaèki Institut, Division of Pharmacology, Prilaz Baruna Filipoviaæ 25, 10000 Zagreb, Croatia.

3 Pfizer Global Research & Development, Discovery Biology, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.

0022-3565/02/3033-1130$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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