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

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.

Experimental approach: 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.

Key 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 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.

Figure 1

Pharmacokinetic (PK) models accounting for enterohepatic recycling. (a) PK model for diclofenac and its metabolite 4-hydroxydiclofenac. CMT1 represents the administration site for p.o. dosing, CMT6 represents the administration site for i.p. dosing, CMT2 represents the central compartment for the parent, CMT7 describes the disposition of the parent, CMT4 represents the central compartment for the metabolite, CMT5 describes the disposition of the metabolite and CMT3 represents the enterohepatic recirculation (EHC) compartment. The periodic transfer rate of EHC to central compartment is a nonlinear function (k₃₂^*X(t)and k₃₄^*X(t)). See PK data analysis for further details. (b) Mixture model with a conversion compartment for rofecoxib. CMT1–CMT3 depict the central and peripheral compartments, respectively. CMT5 and CMT6 represent the depot compartments following i.p. and p.o. administration of rofecoxib. EHC is described by CMT4, T_lag is the lag time associated with the start of EHC and k_recycling the re-absorption rate constant. F₄–F₆ are estimates of the bioavailability for compartments 4–6, respectively. Dashed arrow represents administration of a fictitious dose into the EHC compartment.

Figure 2

A mixture model approach, which assumes the existence of sub-populations, was used to account for distinct patterns in the kinetic disposition of rofecoxib (10 mg kg⁻¹). The upper panel (a) shows secondary peaks in the concentration vs time profile after i.v. administration, whereas the lower panel (b) illustrates the plateau phase in the concentration vs time profile observed after i.p. administration.

Figure 3

(a) Concentration vs time profile of diclofenac and its metabolite 4-hydroxy diclofenac after a 60-min i.v. infusion of 1 and 2 mg kg⁻¹ dose of diclofenac administered either orally or intraperitoneally. Dose was administered at time zero. The lines represent the population and individual predictions of parent and metabolite according to the oscillatory model described in Figure 1a. (b) Visual predictive check of the model for diclofenac (parent) and its metabolite. The measured plasma concentrations are shown along with lines representing the median population predictions and 2.5 and 97.5% quantiles according to the oscillatory model described in Figure 1a.

Figure 4

(a) Concentration vs time profile of rofecoxib after a 60-min i.v. infusion of 0.5, 10 and 5.95 mg kg⁻¹ and a 5-min i.v. infusion of 10 mg kg⁻¹ dose of rofecoxib administered intraperitoneally and 2 mg kg⁻¹ orally. Dose was administered at time zero. The measured plasma concentrations are shown with lines representing the population and individual predictions according to the recycling model described in Figure 1b. (b) Visual predictive check of the model for rofecoxib. The measured plasma concentrations are shown with lines representing the median population predictions and 2.5 and 97.5% quantiles according to the recycling model described in Figure 1b.

Figure 5

(a) Simulated concentration vs time profile of diclofenac and its 4-hydroxy metabolite after p.o. administration. (b) Simulated PGE₂ inhibition vs time profile based on the competitive interaction model proposed by Holford and Sheiner (1981) (Equation (4), see text for details). The lines represent diclofenac pharmacokinetics (PK) in rats with cannulated bile duct and the PK of diclofenac and its 4-hydroxy metabolite in rats with intact enterohepatic recirculation.

Figure 6

(a) Simulated concentration vs time profile of rofecoxib after i.v. administration. (b) Simulated PGE₂ inhibition vs time profile based on the inhibitory I_max model (Equation (5), see text for details). The lines represent rats with cannulated bile duct and the sub-populations 1 and 2 of rats with intact EHC.