Population pharmacokinetic modelling of the enterohepatic recirculation of diclofenac and rofecoxib in rats.
Br J Pharmacol
; 153(5): 1072-84, 2008 Mar.
Article
en En
| MEDLINE
| ID: mdl-18193075
ABSTRACT
BACKGROUND AND PURPOSE:
Enterohepatic recirculation (EHC) is a common pharmacokinetic phenomenon that has been poorly modelled in animals. The presence of EHC leads to the appearance of multiple peaks in the concentration-time profile and increased exposure, which may have implications for drug effect and extrapolation across species. The aim of this investigation was to develop a population pharmacokinetic model for diclofenac and rofecoxib that describes EHC and to assess its consequence for the pharmacodynamics of both drugs. EXPERIMENTALAPPROACH:
The pharmacokinetics of diclofenac and rofecoxib was characterized in male rats following intravenous, intraperitoneal and oral administration. Blood samples were collected at pre-defined time points after dosing to determine plasma concentrations over time. A parametric approach using nonlinear mixed effects modelling was applied to describe EHC, whilst simulations were used to evaluate its impact on PGE(2) inhibition. KEYRESULTS:
For diclofenac, EHC was described by a compartmental model with periodic transfer rate and metabolite formation rate. For rofecoxib, EHC modelling required a conversion compartment with first-order recycling rate and lag time. Based on model predictions, EHC causes an increase of 95% in the systemic exposure to diclofenac and of 15% in the exposure to rofecoxib. In addition, EHC prolongs the inhibition of PGE(2) and increases the duration of the anti-inflammatory effect (24 h for rofecoxib 10 mg kg(-1)) without affecting maximum inhibition. CONCLUSIONS AND IMPLICATIONS Our findings show the relevance of exploring EHC in a quantitative manner to accurately interpret pharmacodynamic findings in vivo, in particular when scaling across species.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Sulfonas
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Diclofenaco
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Inhibidores de la Ciclooxigenasa
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Circulación Enterohepática
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Inhibidores de la Ciclooxigenasa 2
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Lactonas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Br J Pharmacol
Año:
2008
Tipo del documento:
Article
País de afiliación:
Países Bajos