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Medicines in neonates
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
The binding of drugs to plasma protein is dependent on the concentration of available binding proteins, the affinity constant of the protein(s) for the drug, the number of available binding sites, and the presence of pathophysiologic conditions or endogenous compounds that may alter the drug-protein binding interaction [50–52].
Special Consideration of Drug Disposition
Published in Gary M. Matoren, The Clinical Research Process in the Pharmaceutical Industry, 2020
Other investigators have also concluded that, in the uremic patient, decreased binding of drugs cannot be accounted for on the basis of albumin levels alone. Using equilibrium dialysis to determine protein binding, Craig et al. [26] investigated sulfamethoxazole, dicloxacillin, penicillin G, phenytoin, salicylate, and digitoxin binding in treated and untreated sera from uremic patients and normal subjects. They undertook measurements in serum before and after charcoal treatment at pH 3.0. Treatment of the sera with charcoal did not affect the binding in any way when the serum was from normal subjects. However, charcoal treatment of the serum from uremic subjects led to significantly increased binding in almost every case. Obviously, charcoal treatment had removed one or more substances which either directly or indirectly interfered with protein binding.
Essential Pharmacology of Abused Drugs
Published in Frank Lynn Iber, Alcohol and Drug Abuse as Encountered in Office Practice, 2020
Protein binding holds drug in the serum and retards its movement into the central nervous system and into the liver for metabolic alteration or into the liver and kidney for excretion. All water-soluble agents exhibit some protein binding, but it varies from little (<15%) to marked (>60%). Protein binding diminishes the concentration of drug available for diffusion into the brain and liver, and of course, decreases glomerular filtration at the kidney. Occasionally, albumin binding of a drug is altered by another drug that binds even more tightly, displacing the initial drug. Protein binding is also influenced by conditions that alter blood pH. A highly bound agent requires as much as 20 min for the high to be perceived, even after intravenous administration.
Nanoparticle-protein corona complex: understanding multiple interactions between environmental factors, corona formation, and biological activity
Published in Nanotoxicology, 2021
Aysel Tomak, Selin Cesmeli, Bercem D. Hanoglu, David Winkler, Ceyda Oksel Karakus
Biophysical techniques, such as surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) are well-suited for quantifying the affinity of specific proteins for NPs. SPR allows label-free detection and measurement of NP-protein interactions in real-time. For example, Di Ianni et al. (2017) studied the interactions of lipid-based NPs with blood proteins using SPR. Patra et al. (2016) used SPR to understand the binding kinetics of several plasma components to AuNPs. While highly useful for measuring various affinity/kinetic parameters of NP-protein interactions in real-time, one major drawback of SPR is its inability to detect low molecular weight molecules (Ahmed et al. 2010). ITC is another common technique that can elucidate protein binding kinetics, thermodynamics, and selectivity. This is exemplified by Srinivasan et al. (2014) who employed ITC to study interactions between a specific protein, ubiquitin, and two functionalized NPs. They demonstrated the entropically driven nature of protein binding in both systems. One major drawback of ITC is that it can be difficult to distinguish thermal exchanges due to protein corona formation from those caused by protein denaturation, NP aggregation, or settling. Therefore, an alternative technique is required to confirm results. Huang and Lau (2016) reviewed the recent application of ITC to understanding the thermodynamics of interactions between proteins and several NPs (e.g. Au, ZnO, CuO, Fe3O4 NPs) and highlighted the importance of using complementary techniques to enhance the accuracy, validity, and interpretation of ITC results.
Pharmacokinetics and metabolic disposition of a potent and selective kynurenine monooxygenase inhibitor, CHDI-340246, in laboratory animals
Published in Xenobiotica, 2021
Vinod Khetarpal, Todd Herbst, Diana Shefchek, Steven Ash, Michael Fitzsimmons, Mark Gohdes, Ignacio Munoz-Sanjuan, Celia Dominguez
The extent of protein binding of CHDI-340246 was investigated in pooled human plasma and plasma obtained from 3 individual human donors at 1, 5 and 25 µM concentrations. The binding at a single concentration (5 µM) of CHDI-340246 was also determined in pooled plasma from Sprague Dawley rats, C57BL/6 mice, beagle dogs, and cynomolgus monkey, as well as to human serum albumin (HAS) and α-acid glycoprotein (AAG). In these assays, metoprolol, nicardipine, propranolol and warfarin (all at 10 µM) were used as reference compounds to assure the validity of the assay. All protein binding determinations were carried out using a Rapid Equilibrium Dialysis (RED) plate assay. The compound was incubated with the appropriate matrix at the required concentration and after a 4 hr equilibration period, the compound was quantified in aliquots taken from both sides of the dialysis membrane using LC-MS/MS method. For CHDI-340246, LC-MS/MS method with a lower limit of quantification (LLOQ) of 0.002 µM was developed specifically for the purpose of obtaining accurate values for protein binding.
Hypothesis of using albumin to improve drug efficacy in cancers accompanied by hypoalbuminemia
Published in Xenobiotica, 2021
Soghra Bagheri, Ali A. Saboury
In general, any drug is distributed in different tissues and organs after entering the bloodstream. The distribution pattern depends on physical and physiological processes. In other words, drug distribution depends on the amount of protein binding, pH, systemic and local blood flow, permeability of natural barriers (e.g. blood‐brain) and body composition (Paul 2019; Wanat 2020). In addition to the absolute amount or concentration of plasma proteins, binding to other compounds may affect binding capacity of a protein to a drug (Tesseromatis and Alevizou 2008). Only free (unbound) drug can be distributed throughout the body and have a pharmacological effect (Kok-Yong and Lawrence 2015). Of note, decreased protein binding increases the concentration of the free drug, which in fact increases the part of drug that can penetrate other parts. Of course, this also increases the drug clearance rate. In addition, the presence of larger amounts of free drug in the bloodstream causes the drug to penetrate deeper into tissues and thus increase the volume of distribution (Roberts et al. 2013). For instance, the maximum concentration of esomeprazole in the plasma of patients with hypoalbuminemia (that causes decreased protein binding) in intensive care unit has shown a significant decrease (compared to other patients) and also for these patients a larger Vd and faster clearance has been reported (Tian et al. 2018).