Plasma Protein Binding of Highly Bound Drugs Determined With Equilibrium Gel Filtration of Nonradiolabeled Compounds and LC-MS/MS Detection

Isbell, John; Ding, Yuan; Torrão, Leonel; Gatlik, Ewa; Hoffmann, Laurent; Wipfli, Peter

doi:10.1016/j.xphs.2018.10.004

Cited by 19 publications

(12 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The unbound fractions of RPG and QCT in plasma (f uP ) and hepatic microsomes (f uMIC ) were measured through an equilibrium dialysis method using a rapid equilibrium dialysis (RED) device (Thermo Fisher Scientific, Inc., Waltham, MA, USA) as described previously [ 30 , 31 , 32 , 33 ]. The microsomes and 20-fold diluted plasma were spiked with either RPG alone or in combination with QCT yielding final concentrations of 5 μM for both compounds.…”

Section: Methodsmentioning

confidence: 99%

Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

et al. 2021

View full text Add to dashboard Cite

Repaglinide (RPG), a rapid-acting meglitinide analog, is an oral hypoglycemic agent for patients with type 2 diabetes mellitus. Quercetin (QCT) is a well-known antioxidant and antidiabetic flavonoid that has been used as an important ingredient in many functional foods and complementary medicines. This study aimed to comprehensively investigate the effects of QCT on the metabolism of RPG and its underlying mechanisms. The mean (range) IC50 of QCT on the microsomal metabolism of RPG was estimated to be 16.7 (13.0–18.6) μM in the rat liver microsome (RLM) and 3.0 (1.53–5.44) μM in the human liver microsome (HLM). The type of inhibition exhibited by QCT on RPG metabolism was determined to be a mixed inhibition with a Ki of 72.0 μM in RLM and 24.2 μM in HLM as obtained through relevant graphical and enzyme inhibition model-based analyses. Furthermore, the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of RPG administered intravenously and orally in rats were significantly increased by 1.83- and 1.88-fold, respectively, after concurrent administration with QCT. As the protein binding and blood distribution of RPG were observed to be unaltered by QCT, it is plausible that the hepatic first-pass and systemic metabolism of RPG could have been inhibited by QCT, resulting in the increased systemic exposure (AUC and Cmax) of RPG. These results suggest that there is a possibility that clinically significant pharmacokinetic interactions between QCT and RPG could occur, depending on the extent and duration of QCT intake from foods and dietary supplements.

show abstract

Section: Methodsmentioning

confidence: 99%

Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The PPBR is indicative of the quantity of unbound drug, which reflects the pharmacodynamic activity of a drug. Moreover, the PPBR can influence drug clearance in the body; PPBR data are required for the prediction of human clearance based on IVIVE [25,26]. The prediction of human PK/PD from animal data is a mandatory requirement when considering interspecies PPBR values.…”

Section: Resultsmentioning

confidence: 99%

Determining the Drug-Like Properties of Ailanthone, a Novel Chinese Medicine Monomer with Anti-CRPC Activity

Guo

Xie

et al. 2020

Planta Med

View full text Add to dashboard Cite

Approximately 40% of compounds with therapeutic potential cannot be successfully developed into drugs owing to their poor pharmaceutical properties, emphasising the need to profile their drug-like properties as early as possible during preclinical development. This study aimed to evaluate the drug-like properties of ailanthone, a novel Chinese medicine monomer that was shown to have activity against castration-resistant prostate cancer tumour growth and metastasis in our previous study. The drug-like properties detected in the present study included effects on permeability, liver microsome stability, plasma protein binding rate, plasma stability, and human ether-à-go-go-related gene inhibition. Additionally, the following results were obtained: the efflux ratio of ailanthone was > 32 during permeability detection; the half-life and intrinsic clearance (Clint) in mouse, rat, and human liver microsomes were > 145 min and < 9.6 µL/min/mg protein, respectively. The Clint(liver) of ailanthone was < 38.0, < 17.3, and < 8.6 mL/min/kg body weight in mice, rats, and humans, respectively. The plasma protein binding percentage of ailanthone was 16.6 ± 4.2% in human plasma, with 62.5% remaining at 120 min after incubation. The IC50 value of ailanthone for the human ether-à-go-go-related gene channels was > 30 µM. Collectively, these results and those from our previous study indicate that the pharmacokinetic properties of ailanthone are suitable for the potential development of this compound as an oral or intravenous drug for the treatment of castration-resistant prostate cancer.

show abstract

“…UF methodologies use semipermeable membranes with a specific molecular weight cut-off, which allow retaining proteins from the filtered sample. When a drug-containing plasma sample is placed in the UF apparatus, plasma proteins and all the compounds bound to them are retained; small molecules and unbound drugs pass through the filter membrane after a soft centrifugation [ 62 ]. The UF approach is fast, simple, and can be used to process many samples simultaneously.…”

Section: Analytical Tools For the Evaluation Of Asms’ Free Drug Fractionmentioning

confidence: 99%

The Effect of Plasma Protein Binding on the Therapeutic Monitoring of Antiseizure Medications

et al. 2021

View full text Add to dashboard Cite

Epilepsy is a widely diffused neurological disorder including a heterogeneous range of syndromes with different aetiology, severity and prognosis. Pharmacological treatments are based on the use, either in mono- or in polytherapy, of antiseizure medications (ASMs), which act at different synaptic levels, generally modifying the excitatory and/or inhibitory response through different action mechanisms. To reduce the risk of adverse effects and drug interactions, ASMs levels should be closely evaluated in biological fluids performing an appropriate Therapeutic Drug Monitoring (TDM). However, many decisions in TDM are based on the determination of the total drug concentration although measurement of the free fraction, which is not bound to plasma proteins, is becoming of ever-increasing importance since it correlates better with pharmacological and toxicological effects. Aim of this work has been to review methodological aspects concerning the evaluation of the free plasmatic fraction of some ASMs, focusing on the effect and the clinical significance that drug-protein binding has in the case of widely used drugs such as valproic acid, phenytoin, perampanel and carbamazepine. Although several validated methodologies are currently available which are effective in separating and quantifying the different forms of a drug, prospective validation studies are undoubtedly needed to better correlate, in real-world clinical contexts, pharmacokinetic monitoring to clinical outcomes.

show abstract

Plasma Protein Binding of Highly Bound Drugs Determined With Equilibrium Gel Filtration of Nonradiolabeled Compounds and LC-MS/MS Detection

Cited by 19 publications

References 34 publications

Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

Determining the Drug-Like Properties of Ailanthone, a Novel Chinese Medicine Monomer with Anti-CRPC Activity

The Effect of Plasma Protein Binding on the Therapeutic Monitoring of Antiseizure Medications

Contact Info

Product

Resources

About