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Sami Haddad - One of the best experts on this subject based on the ideXlab platform.
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hepatocyte composition based model as a mechanistic tool for predicting the cell suspension aqueous phase partition coefficient of drugs in in vitro Metabolic Studies
Journal of Pharmaceutical Sciences, 2013Co-Authors: Patrick Poulin, Sami HaddadAbstract:This study is an extension of a previously published microsome composition-based model by Poulin and Haddad (Poulin and Haddad. 2011. J Pharm Sci 100:4501-4517), which was converted to the hepatocyte composition-based model. The first objective was to investigate the ability of the composition-based model to predict nonspecific binding of drugs in hepatocytes suspended in the incubation medium in in vitro Metabolic Studies. The hepatocyte composition-based model describes the cell suspension-aqueous phase partition coefficients, which were used to estimate fraction unbound in the incubation medium (fuinc ) for each drug. The second objective was to make a comparative analysis between the proposed hepatocyte composition-based model and an empirical regression equation published in the literature by Austin et al. (Austin RP, Barton P, Mohmed S, Riley RJ. 2004. Drug Metab Dispos 33:419-425). The assessment was confined by the availability of experimentally determined in vitro fuinc values at diverse hepatocyte concentrations for 92 drugs. The model that made use of hepatocyte composition data provides comparable or superior prediction performance compared with the regression equation that relied solely on physicochemical data; therefore, this demonstrates the ability of predicting fuinc also based on mechanisms of drug tissue distribution. The accuracy of the predictions differed depending on the class of drugs (neutrals vs. ionized drugs) and species (rat vs. human) for each method. This study for hepatocytes corroborates a previous study for microsomes. Overall, this work represents a significant first step toward the development of a generic and mechanistic calculation method of fuinc in incubations of hepatocytes, which should facilitate rational interindividual and interspecies extrapolations of fuinc by considering differences in lipid composition of hepatocytes, for clearance prediction in the physiologically-based pharmacokinetics (PBPK) models.
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pharmacokinetics pharmacodynamics and drug transport and metabolismhepatocyte composition based model as a mechanistic tool for predicting the cell suspension aqueous phase partition coefficient of drugs in in vitro Metabolic Studies
Journal of Pharmaceutical Sciences, 2013Co-Authors: Patrick Poulin, Sami HaddadAbstract:This study is an extension of a previously published microsome composition-based model by Poulin and Haddad (Poulin and Haddad. 2011. J Pharm Sci 100:4501–4517), which was converted to the hepatocyte composition-based model. The first objective was to investigate the ability of the composition-based model to predict nonspecific binding of drugs in hepatocytes suspended in the incubation medium in in vitro Metabolic Studies. The hepatocyte composition-based model describes the cell suspension-aqueous phase partition coefficients, which were used to estimate fraction unbound in the incubation medium (fuinc) for each drug. The second objective was to make a comparative analysis between the proposed hepatocyte composition-based model and an empirical regression equation published in the literature by Austin et al. (Austin RP, Barton P, Mohmed S, Riley RJ. 2004. Drug Metab Dispos 33:419–425). The assessment was confined by the availability of experimentally determined in vitro fuinc values at diverse hepatocyte concentrations for 92 drugs. The model that made use of hepatocyte composition data provides comparable or superior prediction performance compared with the regression equation that relied solely on physicochemical data; therefore, this demonstrates the ability of predicting fuinc also based on mechanisms of drug tissue distribution. The accuracy of the predictions differed depending on the class of drugs (neutrals vs. ionized drugs) and species (rat vs. human) for each method. This study for hepatocytes corroborates a previous study for microsomes. Overall, this work represents a significant first step toward the development of a generic and mechanistic calculation method of fuinc in incubations of hepatocytes, which should facilitate rational interindividual and interspecies extrapolations of fuinc by considering differences in lipid composition of hepatocytes, for clearance prediction in the physiologically-based pharmacokinetics (PBPK) models. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2806–2818, 2013
Patrick Poulin - One of the best experts on this subject based on the ideXlab platform.
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hepatocyte composition based model as a mechanistic tool for predicting the cell suspension aqueous phase partition coefficient of drugs in in vitro Metabolic Studies
Journal of Pharmaceutical Sciences, 2013Co-Authors: Patrick Poulin, Sami HaddadAbstract:This study is an extension of a previously published microsome composition-based model by Poulin and Haddad (Poulin and Haddad. 2011. J Pharm Sci 100:4501-4517), which was converted to the hepatocyte composition-based model. The first objective was to investigate the ability of the composition-based model to predict nonspecific binding of drugs in hepatocytes suspended in the incubation medium in in vitro Metabolic Studies. The hepatocyte composition-based model describes the cell suspension-aqueous phase partition coefficients, which were used to estimate fraction unbound in the incubation medium (fuinc ) for each drug. The second objective was to make a comparative analysis between the proposed hepatocyte composition-based model and an empirical regression equation published in the literature by Austin et al. (Austin RP, Barton P, Mohmed S, Riley RJ. 2004. Drug Metab Dispos 33:419-425). The assessment was confined by the availability of experimentally determined in vitro fuinc values at diverse hepatocyte concentrations for 92 drugs. The model that made use of hepatocyte composition data provides comparable or superior prediction performance compared with the regression equation that relied solely on physicochemical data; therefore, this demonstrates the ability of predicting fuinc also based on mechanisms of drug tissue distribution. The accuracy of the predictions differed depending on the class of drugs (neutrals vs. ionized drugs) and species (rat vs. human) for each method. This study for hepatocytes corroborates a previous study for microsomes. Overall, this work represents a significant first step toward the development of a generic and mechanistic calculation method of fuinc in incubations of hepatocytes, which should facilitate rational interindividual and interspecies extrapolations of fuinc by considering differences in lipid composition of hepatocytes, for clearance prediction in the physiologically-based pharmacokinetics (PBPK) models.
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pharmacokinetics pharmacodynamics and drug transport and metabolismhepatocyte composition based model as a mechanistic tool for predicting the cell suspension aqueous phase partition coefficient of drugs in in vitro Metabolic Studies
Journal of Pharmaceutical Sciences, 2013Co-Authors: Patrick Poulin, Sami HaddadAbstract:This study is an extension of a previously published microsome composition-based model by Poulin and Haddad (Poulin and Haddad. 2011. J Pharm Sci 100:4501–4517), which was converted to the hepatocyte composition-based model. The first objective was to investigate the ability of the composition-based model to predict nonspecific binding of drugs in hepatocytes suspended in the incubation medium in in vitro Metabolic Studies. The hepatocyte composition-based model describes the cell suspension-aqueous phase partition coefficients, which were used to estimate fraction unbound in the incubation medium (fuinc) for each drug. The second objective was to make a comparative analysis between the proposed hepatocyte composition-based model and an empirical regression equation published in the literature by Austin et al. (Austin RP, Barton P, Mohmed S, Riley RJ. 2004. Drug Metab Dispos 33:419–425). The assessment was confined by the availability of experimentally determined in vitro fuinc values at diverse hepatocyte concentrations for 92 drugs. The model that made use of hepatocyte composition data provides comparable or superior prediction performance compared with the regression equation that relied solely on physicochemical data; therefore, this demonstrates the ability of predicting fuinc also based on mechanisms of drug tissue distribution. The accuracy of the predictions differed depending on the class of drugs (neutrals vs. ionized drugs) and species (rat vs. human) for each method. This study for hepatocytes corroborates a previous study for microsomes. Overall, this work represents a significant first step toward the development of a generic and mechanistic calculation method of fuinc in incubations of hepatocytes, which should facilitate rational interindividual and interspecies extrapolations of fuinc by considering differences in lipid composition of hepatocytes, for clearance prediction in the physiologically-based pharmacokinetics (PBPK) models. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2806–2818, 2013
J. M. Harrison - One of the best experts on this subject based on the ideXlab platform.
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the chemistry of 1 1 thiobis 2 chloroethane sulphur mustard part i some simple derivatives
Phosphorus Sulfur and Silicon and The Related Elements, 1992Co-Authors: Robin M. Black, J. M. Harrison, K. Brewster, N. StansfieldAbstract:Abstract Some derivatives of 1,1′-thiobis(2-chloroethane) (sulphur mustard) have been synthesised for use as reference compounds in a wide range of Studies embracing analysis, metabolism, environmental degradation and decontamination. Compounds include products formed by hydrolysis, substitution and elimination reactions and their oxidised sulphoxide and sulphone analogues. A comprehensive series of methylthio, methylsulphinyl and methylsulphonyl derivatives has been synthesised in support of Metabolic Studies.
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the chemistry of 1 1 thiobis 2 chloroethane sulphur mustard part ii 1 the synthesis of some conjugates with cysteine n acetylcysteine and n acetylcysteine methyl ester
Phosphorus Sulfur and Silicon and The Related Elements, 1992Co-Authors: Robin M. Black, K. Brewster, Raymond J. Clarke, J. M. HarrisonAbstract:Abstract The syntheses of a number of conjugates of 1,1′-thiobis(2-chloroethane) (“sulphur mustard”) and its simple derivatives with cysteine, N-acetylcysteine and N-acetylcysteine methyl ester are described. These compounds were synthesised for use as reference compounds to support metabolite identification in Metabolic Studies and, in some cases, to provide standards for analytical procedures being developed for the retrospective confirmation of exposure to sulphur mustard.
Robin M. Black - One of the best experts on this subject based on the ideXlab platform.
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the chemistry of 1 1 thiobis 2 chloroethane sulphur mustard part i some simple derivatives
Phosphorus Sulfur and Silicon and The Related Elements, 1992Co-Authors: Robin M. Black, J. M. Harrison, K. Brewster, N. StansfieldAbstract:Abstract Some derivatives of 1,1′-thiobis(2-chloroethane) (sulphur mustard) have been synthesised for use as reference compounds in a wide range of Studies embracing analysis, metabolism, environmental degradation and decontamination. Compounds include products formed by hydrolysis, substitution and elimination reactions and their oxidised sulphoxide and sulphone analogues. A comprehensive series of methylthio, methylsulphinyl and methylsulphonyl derivatives has been synthesised in support of Metabolic Studies.
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the chemistry of 1 1 thiobis 2 chloroethane sulphur mustard part ii 1 the synthesis of some conjugates with cysteine n acetylcysteine and n acetylcysteine methyl ester
Phosphorus Sulfur and Silicon and The Related Elements, 1992Co-Authors: Robin M. Black, K. Brewster, Raymond J. Clarke, J. M. HarrisonAbstract:Abstract The syntheses of a number of conjugates of 1,1′-thiobis(2-chloroethane) (“sulphur mustard”) and its simple derivatives with cysteine, N-acetylcysteine and N-acetylcysteine methyl ester are described. These compounds were synthesised for use as reference compounds to support metabolite identification in Metabolic Studies and, in some cases, to provide standards for analytical procedures being developed for the retrospective confirmation of exposure to sulphur mustard.
N. Stansfield - One of the best experts on this subject based on the ideXlab platform.
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the chemistry of 1 1 thiobis 2 chloroethane sulphur mustard part i some simple derivatives
Phosphorus Sulfur and Silicon and The Related Elements, 1992Co-Authors: Robin M. Black, J. M. Harrison, K. Brewster, N. StansfieldAbstract:Abstract Some derivatives of 1,1′-thiobis(2-chloroethane) (sulphur mustard) have been synthesised for use as reference compounds in a wide range of Studies embracing analysis, metabolism, environmental degradation and decontamination. Compounds include products formed by hydrolysis, substitution and elimination reactions and their oxidised sulphoxide and sulphone analogues. A comprehensive series of methylthio, methylsulphinyl and methylsulphonyl derivatives has been synthesised in support of Metabolic Studies.