Drug–Drug Interactions Related to Altered Absorption and Plasma Protein Binding: Theoretical and Regulatory Considerations, and an Industry Perspective

Hochman, Jerome H.; Tang, Cuyue; Prueksaritanont, Thomayant

doi:10.1002/jps.24306

Cited by 22 publications

(17 citation statements)

References 110 publications

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“…Usually, only unbound molecules are available for diffusion across cell membranes and consequently could interact with pharmacological targets. Moreover, the level of plasma protein binding of drugs influences not only their action but also their disposition and efficacy [ 33 , 34 , 35 ]. In this study, ADMET analyses have showed that most molecules isolated from F. carica are strongly bound to plasma proteins.…”

Section: Resultsmentioning

confidence: 99%

A specific QSAR model for proteasome inhibitors from Oleaeuropaea and Ficuscarica

et al. 2018

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Oleaeuropaea and Ficuscarica are widely used in traditional medicine for the treatment of cancer. Therefore, it is of interest to develop a QSAR model for screening proteasome inhibitors from plant source. Hence, a QSAR model was developed using multiple linear regressions; partial least squares regression and principal component regression methods. Results of QSAR modeling and docking demonstrate that compounds derived from both plants have great potentiality to be proteasome inhibitors. The developed QSAR model highlights a strong structure-effect relationship. The predicted correlation of comparative molecular field analysis, and comparative molecular similarity indexes are 0.963 and 0.919, respectively. Computed absorption, distribution, metabolism, excretion and toxicity studies on these derivatives showed encouraging results with very low toxicity, distribution and absorption.

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Section: Resultsmentioning

confidence: 99%

A specific QSAR model for proteasome inhibitors from Oleaeuropaea and Ficuscarica

et al. 2018

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“…Therefore this can be considered as a drug related risk factor, similarly to the drug transporters (e.g. P-gp) affinity, protein binding, high lipophilicity and consequent significant heart tissue penetration [ 148 – 150 ]. Assessment of the pharmacodynamic effects of the drug interactions is much more challenging due to the significant diversity in the endpoints which should be analyzed depending on the clinical effect.…”

Section: Discussionmentioning

confidence: 99%

Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect - comprehensive overview of clinical trials

Wiśniowska

Tylutki

Wyszogrodzka

et al. 2016

BMC Pharmacol Toxicol

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Background: Proarrhythmia assessment is one of the major concerns for regulatory bodies and pharmaceutical industry. ICH guidelines recommending preclinical tests have been established in attempt to eliminate the risk of drug-induced arrhythmias. However, in the clinic, arrhythmia occurrence is determined not only by the inherent property of a drug to block ion currents and disturb electrophysiological activity of cardiac myocytes, but also by many other factors modifying individual risk of QT prolongation and subsequent proarrhythmia propensity. One of those is drug-drug interactions. Since polypharmacy is a common practice in clinical settings, it can be anticipated that there is a relatively high risk that the patient will receive at least two drugs mutually modifying their proarrhythmic potential and resulting either in triggering the occurrence or mitigating the clinical symptoms. The mechanism can be observed either directly at the pharmacodynamic level by competing for the molecular targets, or indirectly by modifying the physiological parameters, or at the pharmacokinetic level by alteration of the active concentration of the victim drug. Methods: This publication provides an overview of published clinical studies on pharmacokinetic and/or pharmacodynamic drug-drug interactions in humans and their electrophysiological consequences (QT interval modification). Databases of PubMed and Scopus were searched and combinations of the following keywords were used for Title, Abstract and Keywords fields: interaction, coadministration, combination, DDI and electrocardiographic, QTc interval, ECG. Only human studies were included. Over 4500 publications were retrieved and underwent preliminary assessment to identify papers accordant with the topic of this review. 76 papers reporting results for 96 drug combinations were found and analyzed.

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“…Since most of warfarin molecules in blood are bound to HSA (>99%) [ 7 ] the presence of another compound which also binds to HSA can theoretically cause displacement of warfarin leading to elevation of free warfarin concentration [ 8 , 9 ]. These interactions could lead to adverse effects in patients suffering from a kidney or liver disease [ 10 , 11 , 12 ]. Although some of the aforementioned in vitro data implies otherwise, displacement of warfarin from HSA is regarded as clinically insignificant under the normal dosing regime [ 11 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Warfarin and Flavonoids Do Not Share the Same Binding Region in Binding to the IIA Subdomain of Human Serum Albumin

et al. 2017

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Human serum albumin (HSA) binds a variety of xenobiotics, including flavonoids and warfarin. The binding of another ligand to the IIA binding site on HSA can cause warfarin displacement and potentially the elevation of its free concentration in blood. Studies dealing with flavonoid-induced warfarin displacement from HSA provided controversial results: estimated risk of displacement ranged from none to serious. To resolve these controversies, in vitro study of simultaneous binding of warfarin and eight different flavonoid aglycons and glycosides to HSA was carried out by fluorescence spectroscopy as well as molecular docking. Results show that warfarin and flavonoids do not share the same binding region in binding to HSA. Interactions were only observed at high warfarin concentrations not attainable under recommended dosing regimes. Docking experiments show that flavonoid aglycons and glycosides do not bind at warfarin high affinity sites, but rather to different regions within the IIA HSA subdomain. Thus, the risk of clinically significant warfarin–flavonoid interaction in binding to HSA should be regarded as negligible.

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Drug–Drug Interactions Related to Altered Absorption and Plasma Protein Binding: Theoretical and Regulatory Considerations, and an Industry Perspective

Cited by 22 publications

References 110 publications

A specific QSAR model for proteasome inhibitors from Oleaeuropaea and Ficuscarica

A specific QSAR model for proteasome inhibitors from Oleaeuropaea and Ficuscarica

Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect - comprehensive overview of clinical trials

Warfarin and Flavonoids Do Not Share the Same Binding Region in Binding to the IIA Subdomain of Human Serum Albumin

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