Population pharmacokinetic modelling of the enterohepatic recirculation of diclofenac and rofecoxib in rats.
OBJECTIVE
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.


METHODS
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.


RESULTS
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
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.
Huntjens
D R H
DR
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
Strougo
A
A
Chain
A
A
Metcalf
A
A
Summerfield
S
S
Spalding
D J M
DJ
Danhof
M
M
Della Pasqua
O
O
D000284:Administration, Oral; D000818:Animals; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004008:Diclofenac / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004764:Enterohepatic Circulation; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D007783:Lactones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D004008:Diclofenac; D015232:Dinoprostone