Vol. 297, Issue 1, 198-205, April 2001

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

Mariona Josa, José Pérez Urizar, Javier Rapado, Carmen Dios-Viéitez, Gilberto Castañeda-Hernández, Francisco Flores-Murrieta, María Jesús Renedo and Iñaki F. Trocóniz

Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona, Spain (M.J., J.R., C.D-V., M.J.R., I.F.T.); Department of Pharmacology and Toxicology, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico (J.P.U., G.C.H.); and Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico (F.F.-M.)

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 IC₅₀ [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.