In vitro, in silico and integrated strategies for the estimation of plasma protein binding. A review

Lambrinidis, George; Vallianatou, Theodosia; Tsantili‐Kakoulidou, Anna

doi:10.1016/j.addr.2015.03.011

Cited by 119 publications

(112 citation statements)

References 198 publications

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“…It is also important to have the ability to estimate these in vitro properties from the chemical structure thus helping the design stage of the molecules too. It has been shown that the retention of compounds obtained on the proposed biomimetic stationary phases can be estimated in silico [52][53][54][55], however it is worth noting that the in silico models use 2D molecular descriptors that are not sufficient to estimate the 3D contribution of the molecules binding to proteins, therefore they can be used only as a rough estimations.…”

Section: Introductionmentioning

confidence: 99%

In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

Valkó¹,

Teague²,

Pidgeon³

2017

ADMET DMPK

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Section: Introductionmentioning

confidence: 99%

In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

Valkó¹,

Teague²,

Pidgeon³

2017

ADMET DMPK

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“…ANK6, tANK6, as well as cANK6r bound to AGP (K D between 0.06 and 0.29 μ M) much stronger than to HSA (K D of 138 μ M and higher). This had been expected before as all three -peptides have a positive net charge and AGP is known to more strongly bind positively charged molecules as compared to HSA, which is known to bind rather acidic or neutral molecules [ 40 ]. This had been observed previously for D3 in a similar manner.…”

Section: Discussionmentioning

confidence: 71%

In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer’s Disease

Schartmann

Schemmert

Niemietz

et al. 2018

JAD

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Diffusible amyloid-β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer’s disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely -enantiomeric peptide D3 and its derivatives as AD drug candidates. Here, we compare one of the most promising D3 derivatives, ANK6, with its tandem version (tANK6), and its head-to-tail cyclized isoform (cANK6r). In vitro tests investigating the -peptides’ potencies to inhibit Aβ aggregation, eliminate Aβ oligomers, and reduce Aβ-induced cytotoxicity revealed that all three -peptides efficiently target Aβ. Subsequent preclinical pharmacokinetic studies of the three all--peptides in wildtype mice showed promising blood-brain barrier permeability with cANK6r yielding the highest levels in brain. The peptides’ potencies to lower Aβ toxicity and their remarkable brain/plasma ratios make them promising AD drug candidates.

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“…The PPB, with NSB correction, was 92.9 ± 1.3 and 99.38 ± 0.09% for the spiked rat plasma GOV concentrations at low and high concentrations, respectively. As it was stated by Chandasana et al [9] and Lambrinidis et al [29] PPB can influence the clearance of drug in the body, thereby those extended PPB are probably been responsible for the medium clearance previously described. In addition, such high PPB could enable slow distribution into the intra-and extracellular space [18].…”

Section: Conditionsmentioning

confidence: 67%

“…PPB is the distribution indicative of unbound drug which reflects the pharmacodynamically active drug with consequences in overall pharmacological action. The knowledge of plasma protein binding remains important throughout a drug discovery and development project, but should be integrated to pharmacokinetic data [9,18,29]. There are several in vitro methods for measuring the unbound fraction in plasma and, ultrafiltration is one of the most commonly used [27].…”

Section: Conditionsmentioning

confidence: 99%

Pharmacokinetic properties, in vitro metabolism and plasma protein binding of govaniadine an alkaloid isolated from Corydalis govaniana Wall

Marques

Callejon

Pinto³

et al. 2016

Journal of Pharmaceutical and Biomedical Analysis

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Govaniadine (GOV) is an alkaloid isolated from Corydalis govaniana Wall. It has been reported to show a different number of biological activities including anti-urease, leishmanicidal and antinociceptive. The present study aims to characterize the GOV in vitro metabolism after incubation with rat and human liver microsomes (RLM and HLM, respectively) and to evaluate its pharmacokinetic properties. The identification of GOV metabolites was conducted by different mass analyzers: a micrOTOF II-ESI-ToF Bruker Daltonics and an amaZon-SL ion trap (IT) Bruker Daltonics. For the pharmacokinetic study of GOV in rats after intravenous administration, a LC-MS/MS method was developed and applied to. The analyses were performed using an Acquity UPLC coupled to an Acquity TQD detector equipped with an ESI interface. The liver microsomal incubation resulted in new O-demethylated, di-hydroxylated and mono-hydroxylated compounds. Regarding the method validation, the calibration curve was linear over the concentration range of 2.5-3150.0ngmL, with a lower limit of quantitation (LLOQ) of 2.5ngmL. This method was successfully applied to a pharmacokinetic study. The profile was best fitted to a two-compartment model, the first phase with a high distribution rate constant (α) 0.139±0.086min, reflected by the short distribution half-life (t1/2α) 9.2±8.9min and the later one, with an elimination half-life (t1/2β) 55.1±37.9min. The main plasma protein binding was 96.1%. This is a first report in this field and it will be useful for further development of govaniadine as a drug candidate.

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In vitro, in silico and integrated strategies for the estimation of plasma protein binding. A review

Cited by 119 publications

References 198 publications

In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer’s Disease

Pharmacokinetic properties, in vitro metabolism and plasma protein binding of govaniadine an alkaloid isolated from Corydalis govaniana Wall

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