Anomalous relationship between free drug fraction and its total concentration in drug–protein systems

Dawidowicz, Andrzej L.; Kobielski, Mateusz; Pieniadz, Jaroslaw

doi:10.1016/j.ejps.2008.06.011

Cited by 13 publications

(15 citation statements)

References 19 publications

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“…[6][7][8] The blood cell-plasma partition coefficient p (Eq. 2) is also considered as concentration independent because the plasma concentrations of compounds are relatively low.…”

Section: Description Of the Methodsmentioning

confidence: 99%

A Convenient Method to Measure Blood–Plasma Concentration Ratio Using Routine Plasma Collection in In Vivo Pharmacokinetic Studies

Berezhkovskiy¹,

Zhang²,

Cheong³

2011

Journal of Pharmaceutical Sciences

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“…[6][7][8] The blood cell-plasma partition coefficient p (Eq. 2) is also considered as concentration independent because the plasma concentrations of compounds are relatively low.…”

Section: Description Of the Methodsmentioning

confidence: 99%

A Convenient Method to Measure Blood–Plasma Concentration Ratio Using Routine Plasma Collection in In Vivo Pharmacokinetic Studies

Berezhkovskiy¹,

Zhang²,

Cheong³

2011

Journal of Pharmaceutical Sciences

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“…b Fraction unbound estimates in rat plasma and rat liver microsomes were obtained using in silico models developed at Pfizer as described previously with human liver microsomes (Gao et al, 2008). Literature free fraction of indomethacin in rat plasma is 0.040 (Dawidowicz et al, 2008), indicating high confidence in the in silico predictions. selected virtual indomethacin analogs 2, 3, and 4, in which we resorted to introducing electron-deficient or polar amide substituents as standard tactics used in medicinal chemistry to build metabolic resistance around soft spots.…”

Section: Discussionmentioning

confidence: 99%

Utility of MetaSite in Improving Metabolic Stability of the Neutral Indomethacin Amide Derivative and Selective Cyclooxygenase-2 Inhibitor 2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-phenethyl-acetamide

Boyer

Bauman²,

Walker³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Prediction of the metabolic sites for new compounds, synthesized or virtual, is important in the rational design of compounds with increased resistance to metabolism. The aim of the present investigation was to use rational design together with MetaSite, an in silico tool for predicting metabolic soft spots, to synthesize compounds that retain their pharmacological effects but are metabolically more stable in the presence of cytochrome P450 (P450) enzymes. The model compound for these studies was the phenethyl amide (1) derivative of the nonsteroidal anti-inflammatory drug (NSAID) indomethacin. Unlike the parent NSAID, 1 is a potent and selective cyclooxygenase-2 (COX-2) inhibitor and nonulcerogenic anti-inflammatory agent in the rat. This pharmacological benefit is offset by the finding that 1 is very unstable in rat and human microsomes because of extensive P4503 A4/2D6-mediated metabolism on the phenethyl group, experimental observations that were accurately predicted by MetaSite. The information was used to design analogs with polar (glycinyl) and/or electron-deficient (fluorophenyl, fluoropyridinyl) amide substituents to reduce metabolism in 1. MetaSite correctly predicted the metabolic shift from oxidation on the amide substituent to O-demethylation for these compounds, whereas rat and human microsomal stability studies and pharmacokinetic assessments in the rat confirmed that the design tactics for improving pharmacokinetic attributes of 1 had worked in our favor. In addition, the fluorophenyl and pyridinyl amide derivatives retained the potent and selective COX-2 inhibition demonstrated with 1. Overall, the predictions from MetaSite gave useful information leading to the design of new compounds with improved metabolic properties.In the early drug discovery phase, many compounds have high oxidative metabolic instability mediated by cytochrome P450 (P450) enzymes, which often results in poor oral pharmacokinetics in preclinical species. Whereas high-throughput in vitro microsomal assays that monitor metabolic stability provide a convenient means for "rankordering" large numbers of compounds, information pertaining to identification of "soft spots" for unstable compounds cannot be discerned from such analyses and requires separate metabolite identification studies. Unlike microsomal stability assays, metabolite identification experiments are low-throughput and cannot keep pace with high-speed chemistry efforts. In addition, there are scenarios in which metabolism studies will limit the labile site(s) to a certain region within the molecule. To guide chemists in the right direction, information on the exact metabolic site is often preferred. Therefore, in addition to existing in vitro assays, a value added proposition would be the use of in silico tools to precisely predict regiochemistry of metabolism for compounds (synthesized or only virtual), information that could be used for rational design of pharmacologically active compounds with improved metabolic properties.MetaSite is an in silico tool t...

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“…1 when R o ! 7 Lidocaine binds mostly to AGP, while other mentioned drugs bind mostly to albumin. 3 A seemingly unusual phenomenon of a strong decrease of f u with the increase of total drug concentration was experimentally observed for several drugs at low concentrations.…”

Section: Introductionmentioning

confidence: 99%

On the Possibility of Self-Induction of Drug Protein Binding

Berezhkovskiy¹

2010

Journal of Pharmaceutical Sciences

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Anomalous relationship between free drug fraction and its total concentration in drug–protein systems

Cited by 13 publications

References 19 publications

A Convenient Method to Measure Blood–Plasma Concentration Ratio Using Routine Plasma Collection in In Vivo Pharmacokinetic Studies

A Convenient Method to Measure Blood–Plasma Concentration Ratio Using Routine Plasma Collection in In Vivo Pharmacokinetic Studies

Utility of MetaSite in Improving Metabolic Stability of the Neutral Indomethacin Amide Derivative and Selective Cyclooxygenase-2 Inhibitor 2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-phenethyl-acetamide

On the Possibility of Self-Induction of Drug Protein Binding

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