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.
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.
Authors: Alexander K Berg; Sumithra J Mandrekar; Katie L Allen Ziegler; Elsa C Carlson; Eva Szabo; Mathew M Ames; Daniel Boring; Paul J Limburg; Joel M Reid Journal: J Clin Pharmacol Date: 2013-02-22 Impact factor: 3.126
Authors: Tae Hwan Kim; Soyoung Shin; Cornelia B Landersdorfer; Yong Ha Chi; Soo Heui Paik; Jayhyuk Myung; Rajbharan Yadav; Stefan Horkovics-Kovats; Jürgen B Bulitta; Beom Soo Shin Journal: AAPS J Date: 2015-05-20 Impact factor: 4.009
Authors: David C Montrose; Krishna Kadaveru; Jillian N M Ilsley; Sierra H Root; Thiruchanduri V Rajan; Manish Ramesh; Frank C Nichols; Bruce T Liang; Dmitry Sonin; Arthur R Hand; Simona Zarini; Robert C Murphy; Glenn S Belinsky; Masako Nakanishi; Daniel W Rosenberg Journal: Toxicol Sci Date: 2010-06-18 Impact factor: 4.849