scholarly journals Lack of Correlation between In Vitro and In Vivo Studies on the Inhibitory Effects of (‒)-Sophoranone on CYP2C9 Is Attributable to Low Oral Absorption and Extensive Plasma Protein Binding of (‒)-Sophoranone

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 328
Author(s):  
Yu Fen Zheng ◽  
Soo Hyeon Bae ◽  
Zhouchi Huang ◽  
Soon Uk Chae ◽  
Seong Jun Jo ◽  
...  
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Oral Absorption ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Inhibitory Potential

(‒)-Sophoranone (SPN) is a bioactive component of Sophora tonkinensis with various pharmacological activities. This study aims to evaluate its in vitro and in vivo inhibitory potential against the nine major CYP enzymes. Of the nine tested CYPs, it exerted the strongest inhibitory effect on CYP2C9-mediated tolbutamide 4-hydroxylation with the lowest IC50 (Ki) value of 0.966 ± 0.149 μM (0.503 ± 0.0383 μM), in a competitive manner. Additionally, it strongly inhibited other CYP2C9-catalyzed diclofenac 4′-hydroxylation and losartan oxidation activities. Upon 30 min pre-incubation of human liver microsomes with SPN in the presence of NADPH, no obvious shift in IC50 was observed, suggesting that SPN is not a time-dependent inactivator of the nine CYPs. However, oral co-administration of SPN had no significant effect on the pharmacokinetics of diclofenac and 4′-hydroxydiclofenac in rats. Overall, SPN is a potent inhibitor of CYP2C9 in vitro but not in vivo. The very low permeability of SPN in Caco-2 cells (Papp value of 0.115 × 10−6 cm/s), which suggests poor absorption in vivo, and its high degree of plasma protein binding (>99.9%) may lead to the lack of in vitro–in vivo correlation. These findings will be helpful for the safe and effective clinical use of SPN.

scholarly journals Evaluation of the Pharmacokinetics of the Pancreastatin Inhibitor PSTi8 Peptide in Rats: Integration of In Vitro and In Vivo Findings

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 339
Author(s):  
Guru R. Valicherla ◽  
Roshan A. Katekar ◽  
Shailesh Dadge ◽  
Mohammed Riyazuddin ◽  
Anees A. Syed ◽  
...  
Keyword(s):  
Gender Difference ◽  
Protein Binding ◽  
Blood Plasma ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Liver Microsomes ◽  
Rat Plasma ◽  
Dose Proportionality

PSTi8 is a pancreastatin inhibitory peptide that is effective in the treatment of diabetic models. This study investigates the pharmacokinetic (PK) properties of PSTi8 in Sprague Dawley rats, for the first time. In vitro and in vivo PK studies were performed to evaluate the solubility, stability in plasma and liver microsomes, plasma protein binding, blood–plasma partitioning, bioavailability, dose proportionality, and gender difference in PK. Samples were analyzed using the validated LC-MS/MS method. The solubility of PSTi8 was found to be 9.30 and 25.75 mg/mL in simulated gastric and intestinal fluids, respectively. The protein binding of PSTi8 was estimated as >69% in rat plasma. PSTi8 showed high stability in rat plasma and liver microsomes and the blood–plasma partitioning was >2. The bioavailability of PSTi8 after intraperitoneal and subcutaneous administration was found to be 95.00 ± 12.15 and 78.47 ± 17.72%, respectively, in rats. PSTi8 showed non-linear PK in dose proportionality studies, and has no gender difference in the PK behavior in rats. The high bioavailability of PSTi8 can be due to high water solubility and plasma protein binding, low clearance and volume of distribution. Our in vitro and in vivo findings support the development of PSTi8 as an antidiabetic agent.

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.

In vitro and in vivo irreversible plasma protein binding of beclobric acid enantiomers

Chirality ◽  
1993 ◽  
Vol 5 (3) ◽  
pp. 120-125 ◽  
Author(s):  
Sascha Mayer ◽  
Ernst Mutschler ◽  
Hildegard Spahn-Langguth ◽  
Leslie Z. Benet
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein

scholarly journals Plasma protein binding of phenytoin in the aged: in vivo studies.

1982 ◽  
Vol 13 (3) ◽  
pp. 423-425 ◽  
Author(s):  
M Patterson ◽  
R Heazelwood ◽  
B Smithurst ◽  
MJ Eadie
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
In Vivo Studies

Correlation of in vitro and in vivo plasma protein binding using ultracentrifugation and UPLC-tandem mass spectrometry

The Analyst ◽  
2013 ◽  
Vol 138 (20) ◽  
pp. 6106 ◽  
Author(s):  
Cheruvu Hanumanth Srikanth ◽  
Tridib Chaira ◽  
Sunitha Sampathi ◽  
Sreekumar V. B. ◽  
Ramesh B. Bambal
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Tandem Mass

scholarly journals Effects of DU-6859a, a New Quinolone Antimicrobial, on Theophylline Metabolism in In Vitro and In Vivo Studies

1998 ◽  
Vol 42 (7) ◽  
pp. 1751-1755 ◽  
Author(s):  
Yoshihito Niki ◽  
Kenichi Itokawa ◽  
Osamu Okazaki
Keyword(s):  
Healthy Subjects ◽  
Human Liver ◽  
Liver Microsomes ◽  
Urinary Metabolites ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Metabolite Formation ◽  
Theophylline Metabolism

ABSTRACT In vitro and in vivo studies were conducted to investigate the drug interaction between a new quinolone antimicrobial, DU-6859a, and theophylline (TP). The effect of DU-6859a on TP metabolism was evaluated in vitro by measuring the rate of TP metabolite formation by using human liver microsomes. DU-6859a inhibited the metabolism of TP, especially the formation of 1-methylxanthine, in vitro, but to a lesser extent than other drugs that are known to interact with TP. TP was administered alone (200 mg twice a day [b.i.d.] for 9 days) or in combination with DU-6859a (50 or 100 mg b.i.d. for 5 days) to six healthy subjects. DU-6859a administered at a dose of 50 mg resulted in no changes in serum TP concentrations, and slight increases in serum TP concentrations were observed at a dose of 100 mg. Moreover, the administration of 100 mg of DU-6859a resulted in decreases in all urinary TP metabolites, with significant differences. It appears that although DU-6859a has a weak inhibitory effect on TP metabolism in vitro, its concomitant use with TP at clinical dosage levels does not cause any adverse effects, showing only a slight increase in blood TP concentrations and a decrease in urinary metabolites.

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