Pharmacokinetic/Pharmacodynamic Modeling of Antipyretic and Anti-Inflammatory Effects of Naproxen in the Rat

• Published in: The Journal of pharmacology and experimental therapeutics 2001-04, Vol.297 (1), p.198-205
• Main Authors: Mariona Josa, JoséPérez Urizar, Javier Rapado, Carmen Dios-Viéitez, Gilberto Castañeda-Hernández, Francisco Flores-Murrieta, María Jesús Renedo, Iñaki F. Trocóniz
• Format: Article
• Language: English
• Subjects: Analgesics, Non-Narcotic - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Area Under Curve; Male; Models, Biological; Naproxen - pharmacokinetics; Naproxen - pharmacology; Rats; Rats, Wistar
• ISSN: 0022-3565; 1521-0103

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 ( T a ) is maintained by the balance of fever mediators given by a constant (zero order) rate of synthesis ( K syn ), and a first order rate of degradation ( K out ). After an intraperitoneal injection of lipopolysaccharide, the change in T a was modeled assuming an increase in fever mediators described as an input rate function [IR(t)] estimated nonparametrically. An inhibitory E max 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 by K syn and K out (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 ( K IN ) that can be inhibited by the presence of naproxen in plasma. The sigmoidal E max model also well described the inhibition of K IN by naproxen. Estimates for IC 50 [concentration of naproxen in plasma eliciting half of maximum inhibition of IR(t) or K IN ] were 4.24 and 4.13 μg/ml, for the antipyretic and anti-inflammatory effects, respectively.