Back to Search
Start Over
Pharmacokinetic-pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase-2, in rats.
- Source :
- British Journal of Pharmacology; Jan2010, Vol. 159 Issue 1, p176-187, 12p
- Publication Year :
- 2010
-
Abstract
- <bold>Background and Purpose: </bold>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.<bold>Experimental Approach: </bold>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.<bold>Results: </bold>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).<bold>Conclusions: </bold>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]
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 159
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 64862785
- Full Text :
- https://doi.org/10.1111/j.1476-5381.2009.00508.x