scholarly journals In Vitro ADME, Preclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of RBx14255, a Novel Ketolide with Pharmacodynamics Against Multidrug-Resistant Bacterial Pathogens

2020 ◽  
Vol 23 ◽  
pp. 206-219
Author(s):  
SAMUEL RAJ VETHAKKANI ◽  
Trdib Chaira ◽  
Tarani Barman
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Oral Dosage ◽  
Absolute Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Human Pharmacokinetics ◽  
Infection Models

Purpose: The preclinical pharmacokinetic and pharmacodynamic properties of a potent fluoroketolide RBx14255 against Streptococcus pneumoniae and Haemophilus influenzae was compared with telithromycin and human clinical dose was predicted for preclinical development. Methods: The in vitro pharmacokinetic characterization was performed for solubility, Caco-2 permeability, microsomal stability, CYP inhibition and plasma protein binding. In vivo pharmacokinetic studies were performed in Swiss albino mice, Sprague Dawley rats and Beagle dogs. The pharmacodynamic studies were carried out in mouse against S. pneumoniae in systemic infection and against S. pneumoniae and H. influenzae in rat lung infection models. Results: RBx14255 showed superior potency and efficacy in mouse and rat infection models. RBx14255 showed pH dependent solubility (0.41 mg/mL at pH 6.8 and >1 mg/mL at pH 1.2), moderate Caco-2 permeability (A to B: 12 nm/s) with high efflux ratio. It showed high plasma protein binding (>97%) in mouse and low binding (45-70%) in rat, dog and human. The compound is mainly metabolized through CYP3A4. Pharmacokinetic parameters and absolute bioavailability of both, RBx14255 and telithromycin are similar in mouse. Both the ketolides showed low plasma clearance (18% of the normal hepatic blood flow rate) in mouse, moderate to high clearance in rat and dog. Mean oral bioavailability was high in mouse (≥85%), moderate in rat (RBx14255: 15% and telithromycin: 51%) and high to moderate in dog (RBx14255: 98% and telithromycin: 56%). The predicted efficacious dose for a 70 kg man ranges from 124 mg BID to 226 mg BID. Conclusion: RBx14255 displayed significantly better pharmacodynamics which correlates with the pharmacokinetic properties against S. pneumoniae and H. influenzae as compared to telithromycin. The predicted human efficacious doses are in the range of 124-226 mg, making it amenable to oral dosage form drug in human. This could be a promising clinical candidate for future studies.

scholarly journals Metabolism and plasma protein binding of 16 straight- and branched-chain parabens in in vitro liver and skin models

2020 ◽  
pp. 105051
Author(s):  
Cathy Lester ◽  
Nicola J. Hewitt ◽  
Ursula Müller-Vieira ◽  
Manuela Mayer ◽  
Corie Ellison ◽  
...  
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Branched Chain

Prediction of drug-drug interaction from In vitro plasma protein binding and metabolism

1981 ◽  
Vol 30 (24) ◽  
pp. 3347-3354 ◽  
Author(s):  
Osamu Sugita ◽  
Yasufumi Sawada ◽  
Yuichi Sugiyama ◽  
Tatsuji Iga ◽  
Manabu Hanano
Keyword(s):  
Drug Interaction ◽  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Drug Drug Interaction

Evaluation of oral pharmacokinetics, in vitro metabolism, blood partitioning and plasma protein binding of novel antidiabetic agent, S009-0629 in rats

2018 ◽  
Vol 79 (4) ◽  
pp. 173-183 ◽  
Author(s):  
Guru Raghavendra Valicherla ◽  
Kishan Shamjibhai Italiya ◽  
Chandra Prakash Gupta ◽  
Shachi Mishra ◽  
Mohammed Riyazuddin ◽  
...  
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
In Vitro Metabolism ◽  
Antidiabetic Agent ◽  
Oral Pharmacokinetics

scholarly journals Gallium-68-Labelled Indocyanine Green as a Potential Liver Reserve Imaging Agent

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Yuxiao Xia ◽  
Li Zhang ◽  
Yanhong Zhao ◽  
Xiangdong Liu ◽  
Liang Cai ◽  
...  
Keyword(s):  
Indocyanine Green ◽  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Water Solubility ◽  
Time Points ◽  
Binding Rate ◽  
Very High

Objective. This work evaluated the potential of 68Ga-labelledNOTA-ICG (1,4,7-triazacyclononane-1,4,7-triacetic acid indocyanine green) for liver reserve imaging. Methods. To determine the optimal conditions for generating 68Ga-NOTA-ICG, various reaction parameters were implemented. Quality control analysis was performed using different chromatography techniques. The in vitro and in vivo stability was also measured at specific time points. The radioactivity ratio between n-octanol and water was determined to evaluate the water solubility of 68Ga-NOTA-ICG. The plasma-protein binding rate of the labelled compound was determined by the methanol method. The biodistribution and imaging findings were evaluated in normal animals at different time points after injection. A preliminary imaging evaluation was performed using an animal model of hepatic ischaemia-reperfusion injury, which was confirmed by pathology. Results. 68Ga-NOTA-ICG was prepared with very high radiochemical purity (>98%) by reacting at 90°C for 10 min at pH = 3.5∼4.0, with excellent stability in vivo and in vitro (>95% 3 h postpreparation). The in vitro plasma-protein binding rate of 68Ga-NOTA-ICG was 13.01 ± 0.7%, and it showed strong water solubility log P=−2.01±0.04. We found that in addition to excretion through the biliary tract and intestines, 68Ga-NOTA-ICG can be excreted through the urinary tract. The image quality of 68Ga-NOTA-ICG was very high; imaging agent retained in the area of liver injury could clearly be observed. Conclusion. This is the first report on a 68Ga-labelled NOTA-ICG fragment for liver reserve function studies. This complex has promise as a candidate agent for liver reserve imaging.

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