Characterization of plasma protein binding dissociation with online SPE-HPLC

Li, Ping; Fan, Yiran; Wang, Yunlong; Lu, Yaxin; Yin, Zheng

doi:10.1038/srep14866

Cited by 19 publications

(16 citation statements)

References 23 publications

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“…Moreover, in vitro PPB may not mirror in vivo PPB in the live animal as the structure of the plasma proteins and their affinity to bind substrates can vary with age, disease and /or presence of competing endogenous and exogenous compounds such as dietary constituents or other therapeutic drugs [ 33 , 34 ]. Furthermore, the drug-protein dissociation rate, which can also greatly affect highly PPB drugs [ 35 ], was not determined in this study. Likewise, an additional limitation to this project was the scarcity of confirmed FIP-affected plasma as this impacted upon its availability for use in both the HPLC validation and PPB protocols.…”

Section: Discussionmentioning

confidence: 99%

Assay validation and determination of in vitro binding of mefloquine to plasma proteins from clinically normal and FIP-affected cats

et al. 2020

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The antimalarial agent mefloquine is currently being investigated for its potential to inhibit feline coronavirus and feline calicivirus infections. A simple, high pressure liquid chromatography assay was developed to detect mefloquine plasma concentrations in feline plasma. The assay's lower limit of quantification was 250 ng/mL. The mean ± standard deviation intra-and inter-day precision expressed as coefficients of variation were 6.83 ± 1.75 and 5.33 ± 1.37%, respectively, whereas intra-and inter-day accuracy expressed as a percentage of the bias were 11.40 ± 3.73 and 10.59 ± 3.88%, respectively. Accordingly, this validated assay should prove valuable for future in vivo clinical trials of mefloquine as an antiviral agent against feline coronavirus and feline calicivirus. However, the proportion of mefloquine binding to feline plasma proteins has not been reported. The proportion of drug bound to plasma protein binding is an important concept when developing drug dosing regimens. As cats with feline infectious peritonitis (FIP) demonstrate altered concentrations of plasma proteins, the proportion of mefloquine binding to plasma proteins in both clinically normal cats and FIP-affected cats was also investigated. An in vitro method using rapid equilibrium dialysis demonstrated that mefloquine was highly plasma protein bound in both populations (on average > 99%).

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Section: Discussionmentioning

confidence: 99%

Assay validation and determination of in vitro binding of mefloquine to plasma proteins from clinically normal and FIP-affected cats

et al. 2020

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“…The lower free drug concentration, in turn, shifts the equilibrium of drug-plasma protein binding and leads to a release of drug. Depending on the drug, modeling the kinetics of protein plasma binding can, therefore, be crucial [21]. As, furthermore, nutritional components as well as other drugs administered at the same time can be bound by the same transport proteins, other drugs as well as nutrition can affect free drug concentration and thus efficacy [22].…”

Section: Binding Kinetics To Plasma Proteinsmentioning

confidence: 99%

“…For drugs that slowly dissociate from their targets, the free drug and drug-target will not be in rapid equilibrium. In this case, the traditional PK/PD model may underpredict the drug effect [22], whereas models with time-dependent drug-target binding will be more mechanistic and suitable for analyzing the relationship between drug concentration and efficacy [21]. However, it is challenging to estimate the relationship (i.e., define the function effect E = f(AT), see "Pharmacokinetics and pharmacodynamics") between target occupancy and drug effects.…”

Section: Linking Target Occupancy To Drug Efficacymentioning

confidence: 99%

Multi-scale modeling of drug binding kinetics to predict drug efficacy

Clarelli

Liang

Martinecz

et al. 2019

Cell. Mol. Life Sci.

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Optimizing drug therapies for any disease requires a solid understanding of pharmacokinetics (the drug concentration at a given time point in different body compartments) and pharmacodynamics (the effect a drug has at a given concentration). Mathematical models are frequently used to infer drug concentrations over time based on infrequent sampling and/or in inaccessible body compartments. Models are also used to translate drug action from in vitro to in vivo conditions or from animal models to human patients. Recently, mathematical models that incorporate drug-target binding and subsequent downstream responses have been shown to advance our understanding and increase predictive power of drug efficacy predictions. We here discuss current approaches of modeling drug binding kinetics that aim at improving model-based drug development in the future. This in turn might aid in reducing the large number of failed clinical trials.

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“…Donde los valores de k e y V d /F corresponden a los valores estimados de los L I , L S y promedio de cada parámetro, 125 y 22 corresponden a los valores de punto de corte para evaluar la eficacia de MFX para garantizar la cura bacteriológica y para prevenir la emergencia de cepas resistentes respectivamente y f u es la fracción no unida a proteínas plasmáticas o fracción libre. Las dro-gas con bajo porcentaje de unión a proteínas plasmáticas como MFX (<30%), presentan una cinética de unión a proteínas de tipo lineal (Mehvar, 2005) donde ante una disminución de la concentración de la forma libre, el equilibrio entre la forma libre y la forma unida es un proceso que resulta en una constante e instan-tánea concentración de fármaco en forma libre (Li et al 2015). Así las concentraciones totales en plasma de este tipo de drogas pueden considerarse como farma-cológicamente activas y se puede asumir para la f u de MFX un valor de 1 (Lei et al 2017).…”

Section: Ecuación 13unclassified

Propuesta de una dosis de marbofloxacina para el tratamiento de infecciones asociadas a Escherichia coli en cabras de tres semanas de vida

Dell'elce¹,

Meneguez²,

Castroman³

et al. 2019

FAVE Cs Vet

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Se estimó una dosis de marbofloxacina (MFX) para tratar infecciones gastrointestinales asociadas a Escherichia coli en cabras de tres semanas de vida. La farmacodinamia de MFX sobre E. coli se evaluó in vitro estimando las concentraciones inhibitoria mínima (CIM), bactericida mínima (CBM) y preventiva de mutantes (CPM). Marbofloxacina se administró en cabras de tres semanas de edad por vía subcutánea a una dosis de 2 mg/kg. Los parámetros farmacocinéticos se estimaron mediante análisis no compartimental. La dosis de MFX capaz de proteger al 95% de una población se calculó considerando la distribución poblacional de los parámetros farmacocinéticos. La eficacia de MFX se evaluó con la relación entre el área bajo la curva y la CPM (ABC/CPM) con un valor de corte de 22 h. Los resultados mostraron que la dosis estimada de MFX para alcanzar la remisión clínica de infecciones gastrointestinales causadas por E. coli y prevenir la emergencia de cepas resistentes en el 95% de una población de cabras de tres semanas de vida fue de 3,179 mg/kg, que a los fines prácticos se fijó en 3,5 mg/kg.

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Characterization of plasma protein binding dissociation with online SPE-HPLC

Cited by 19 publications

References 23 publications

Assay validation and determination of in vitro binding of mefloquine to plasma proteins from clinically normal and FIP-affected cats

Assay validation and determination of in vitro binding of mefloquine to plasma proteins from clinically normal and FIP-affected cats

Multi-scale modeling of drug binding kinetics to predict drug efficacy

Propuesta de una dosis de marbofloxacina para el tratamiento de infecciones asociadas a Escherichia coli en cabras de tres semanas de vida

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