1. Pharmacokinetic-pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase-2, in rats.
- Author
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Vásquez-Bahena, DA, Salazar-Morales, UE, Ortiz, MI, Castañeda-Hernández, G, Trocóniz, IF, Vásquez-Bahena, D A, Salazar-Morales, U E, Ortiz, M I, Castañeda-Hernández, G, and Trocóniz, Iñaki F
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PHARMACOKINETICS ,PHARMACODYNAMICS ,ANALGESICS ,DRUG efficacy ,CYCLOOXYGENASE 2 inhibitors ,NOCICEPTORS ,HYPERALGESIA ,LABORATORY rats ,ANIMAL experimentation ,BIOAVAILABILITY ,BIOLOGICAL models ,CHAOS theory ,COMPARATIVE studies ,DICLOFENAC ,DOSE-effect relationship in pharmacology ,INFLAMMATORY mediators ,RESEARCH methodology ,MEDICAL cooperation ,NONSTEROIDAL anti-inflammatory agents ,ORAL drug administration ,POLYSACCHARIDES ,RATS ,RESEARCH ,TIME ,CYCLOOXYGENASE 2 ,EVALUATION research - Abstract
Background and Purpose: This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats.Experimental Approach: Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg*kg(-1) of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg*kg(-1) oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI.Results: A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT=LT(0)/(1 +MED). LT(0) is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 microg*mL(-1).Conclusions: The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics. [ABSTRACT FROM AUTHOR]- Published
- 2010
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