Abstract
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.
Footnotes
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Send reprint requests to: Iñaki F. Trocóniz, Ph.D., Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona 31080, Spain. E-mail:itroconiz{at}unav.es
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M.J. was supported by a fellowship from the ministry of education and culture (AP97, BOE 1998-02-25). J.P.U. is a Consejo Nacional de Ciencia y Tecnologia and Dirección General de Estudios de Postgrado-Universidad Nacional Autónoma de México (DGEP-UNAM) research fellow.
- Abbreviations:
- NSAID
- nonsteroidal anti-inflammatory drugs
- COX
- cyclooxygenase
- PG
- prostaglandin
- Ta
- body temperature
- pd
- pharmacodynamic
- pk
- pharmacokinetic
- lps
- lipopolysaccharide
- CL
- clearance
- AUC
- area under the curve
- Received September 18, 2000.
- Accepted December 12, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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