TY - JOUR T1 - Pharmacokinetic/Pharmacodynamic Modeling of Antipyretic and Anti-Inflammatory Effects of Naproxen in the Rat JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 198 LP - 205 VL - 297 IS - 1 AU - Mariona Josa AU - JoséPérez Urizar AU - Javier Rapado AU - Carmen Dios-Viéitez AU - Gilberto Castañeda-Hernández AU - Francisco Flores-Murrieta AU - María Jesús Renedo AU - Iñaki F. Trocóniz Y1 - 2001/04/01 UR - http://jpet.aspetjournals.org/content/297/1/198.abstract N2 - Pharmacokinetic/pharmacodynamic modeling was used to characterize the antipyretic and anti-inflammatory effects of naproxen in rats. An indirect response model was used to describe the antipyretic effects of naproxen after short intravenous infusions. The model assumes that basal temperature (Ta) is maintained by the balance of fever mediators given by a constant (zero order) rate of synthesis (Ksyn), and a first order rate of degradation (Kout). After an intraperitoneal injection of lipopolysaccharide, the change inTa was modeled assuming an increase in fever mediators described as an input rate function [IR(t)] estimated nonparametrically. An inhibitory Emax model adequately described the inhibition of IR(t) by naproxen. A more complex model was used to describe the anti-inflammatory response of oral naproxen in the carrageenin-induced edema model. Before carrageenin injection, physiological conditions are maintained by a balance of inflammation mediators given byKsyn and Kout(see above). After carrageenin injection, the additional synthesis of mediators is described by IR(t) (see above). Such mediators induced an inflammatory process, which is governed by a first order rate constant (KIN) that can be inhibited by the presence of naproxen in plasma. The sigmoidal Emaxmodel also well described the inhibition ofKIN by naproxen. Estimates for IC50 [concentration of naproxen in plasma eliciting half of maximum inhibition of IR(t) or KIN] were 4.24 and 4.13 μg/ml, for the antipyretic and anti-inflammatory effects, respectively. The American Society for Pharmacology and Experimental Therapeutics ER -