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

British Journal of Pharmacology
D R H HuntjensO E Della Pasqua

Abstract

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. 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. 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...Continue Reading

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Citations

May 18, 2011·Evidence-based Complementary and Alternative Medicine : ECAM·Hironori Ishikawa, Shiro Watanabe
Jun 22, 2010·Toxicological Sciences : an Official Journal of the Society of Toxicology·David C MontroseDaniel W Rosenberg
Mar 19, 2016·Drug Metabolism Reviews·Mohd Yaseen MalikJawahar Lal
Sep 9, 2008·European Journal of Pain : EJP·Dymphy R H HuntjensOscar E Della Pasqua
Feb 26, 2013·Journal of Clinical Pharmacology·Alexander K BergUNKNOWN Cancer Prevention Network
Jul 6, 2016·Pharmaceutical Research·Theodoros PapathanasiouTrine Meldgaard Lund
Nov 15, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Elnaz YaghiniOscar Della Pasqua
Jul 29, 2008·Current Opinion in Anaesthesiology
Dec 30, 2009·Respiratory Physiology & Neurobiology·M CarevZ Dogas

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