A physiologically based pharmacokinetic model for quinoxaline‐2‐carboxylic acid in rats, extrapolation to pigs

Abstract

A multi-compartment physiologically based pharmacokinetic (PBPK) model to describe the disposition of cyadox (CYX) and its metabolite quinoxaline-2-carboxylic acid (QCA) after a single oral administration was developed in rats (200 mg/kg b.w. of CYX). Considering interspecies differences in physiology and physiochemistry, the model efficiency was validated by pharmacokinetic data set in swine. The model included six compartments that were blood, muscle, liver, kidney, adipose, and a combined compartment for the rest of tissues. The model was parameterized using rat plasma and tissue concentration data that were generated from this study. Model simulations were achieved using a commercially available software program (ACSLXL ibero version 3.0.2.1). Results supported the validity of the model with simulated tissue concentrations within the range of the observations. The correlation coefficients of the predicted and experimentally determined values for plasma, liver, kidney, adipose, and muscles in rats were 0.98, 0.98, 0.98, 0.99, and 0.95, respectively. The rat model parameters were then extrapolated to pigs to estimate QCA disposition in tissues and validated by tissue concentration of QCA in swine. The correlation coefficients between the predicted and observed values were over 0.90. This model could provide a foundation for developing more reliable pig models once more data are available.

Estimation of residue depletion of cyadox and its marker residue in edible tissues of pigs using physiologically based pharmacokinetic modelling

“…A PBPK model was recently published for CYA's other metabolite, QCA, in rats and pigs (Yang et al, 2015). In contrast to the present work, it was limited to the description of the kinetics of the metabolite, but not the parent compound.…”

“…Moreover, in the previous model, liver was considered to be the sole site of biotransformation (Yang et al, 2015). Since it had been demonstrated that CYA could be metabolized by intestinal microsomes and microbial flora, and radiotracer was observed both in feces and bile as well as urine (Xu et al, 2012), the present model incorporated A c c e p t e d M a n u s c r i p t these dynamic processes to more comprehensively describe the depletion of CYA and BDCYA in pigs.…”

“…Several PBPK models have been developed to predict veterinary drug residues in food animals (Craigmill, 2003;Buur et al, 2006Buur et al, , 2008Cortright et al, 2009; A c c e p t e d M a n u s c r i p t al., 2011; 2014). All of these models successfully simulated the depletion of parent drug, with only two recent models describing the kinetics of their metabolites (Yang et al, 2013;Yang et al, 2015). To date, no single model has linked the disposition of both moieties which is crucial since food safety is estimated from total drug and metabolite exposure, but is then monitored based only on either the parent drug or one metabolite serving as a marker residue.…”

“…A PBPK model for quinoxaline-2-carboxylic acid (QCA), one of the CYA metabolites was developed in rats and pigs (Yang et al, 2015).…”

An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows

“…In the last decade, PBPK modeling has been widely used in the area of veterinary medicine, from the prediction of drug tissue residues (Huang et al, ; Leavens et al, ; Yang et al, ), estimating the withdrawal time (Buur, Baynes, Smith, & Riviere, ; Yang, Huang, et al, ; Yang, Zhou, et al, ), to facilitating the food safety assessment (Henri, Carrez, Meda, Laurentie, & Sanders, ; Lin, Gehring, Mochel, Lavé, & Riviere, ; Yang, Huang, et al, ; Yang, Zhou, et al, ). In this study, a PBPK model was established for heavy sows based on a previous generic PBPK model for swine and cattle (Li et al, ).…”