Antibody–Prodrug Conjugates with KSP Inhibitors and Legumain‐Mediated Metabolite Formation

2019 ◽  
Vol 25 (35) ◽  
pp. 8208-8213 ◽  
Author(s):  
Hans‐Georg Lerchen ◽  
Beatrix Stelte‐Ludwig ◽  
Sandra Berndt ◽  
Anette Sommer ◽  
Lisa Dietz ◽  
...  
Keyword(s):  
Metabolite Formation ◽  
Ksp Inhibitors

scholarly journals Front Cover: Antibody–Prodrug Conjugates with KSP Inhibitors and Legumain‐Mediated Metabolite Formation (Chem. Eur. J. 35/2019)

2019 ◽  
Vol 25 (35) ◽  
pp. 8171-8171
Author(s):  
Hans‐Georg Lerchen ◽  
Beatrix Stelte‐Ludwig ◽  
Sandra Berndt ◽  
Anette Sommer ◽  
Lisa Dietz ◽  
...  
Keyword(s):  
Metabolite Formation ◽  
Front Cover ◽  
Ksp Inhibitors

scholarly journals Antibody–Prodrug Conjugates with KSP Inhibitors and Legumain‐Mediated Metabolite Formation

2019 ◽  
Vol 25 (35) ◽  
pp. 8175-8175
Author(s):  
Hans‐Georg Lerchen ◽  
Beatrix Stelte‐Ludwig ◽  
Sandra Berndt ◽  
Anette Sommer ◽  
Lisa Dietz ◽  
...  
Keyword(s):  
Metabolite Formation ◽  
Ksp Inhibitors

scholarly journals Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 813
Author(s):  
Yoo-Seong Jeong ◽  
Min-Soo Kim ◽  
Nora Lee ◽  
Areum Lee ◽  
Yoon-Jee Chae ◽  
...  
Keyword(s):  
Gastric Acid ◽  
Pbpk Model ◽  
Pbpk Modeling ◽  
Drug Candidate ◽  
Metabolite Formation ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.

Fine-tuning of microsolvation and hydrogen bond interaction regulates substrate channelling in the course of flavonoid biosynthesis

2016 ◽  
Vol 18 (15) ◽  
pp. 10337-10345 ◽  
Author(s):  
Julien Diharce ◽  
Jérôme Golebiowski ◽  
Sébastien Fiorucci ◽  
Serge Antonczak
Keyword(s):  
Hydrogen Bond ◽  
Natural Compounds ◽  
Flavonoid Biosynthesis ◽  
Fine Tuning ◽  
Efficient Production ◽  
Substrate Channeling ◽  
Metabolite Formation ◽  
Hydrogen Bond Interaction ◽  
Bond Interaction ◽  
Substrate Channelling

In the course of metabolite formation, some multienzymatic edifices, the so-called metabolon, are formed and lead through substrate channeling to a more efficient production of the natural compounds.

Molecular cytotoxic mechanisms of chlorpromazine in isolated rat hepatocytes

2013 ◽  
Vol 91 (1) ◽  
pp. 56-63 ◽  
Author(s):  
Stephanie L. MacAllister ◽  
Cheryl Young ◽  
Anna Guzdek ◽  
Nickholas Zhidkov ◽  
Peter J. O'Brien
Keyword(s):  
First Generation ◽  
Rat Hepatocytes ◽  
Antipsychotic Agents ◽  
Toxic Metabolite ◽  
Quinone Oxidoreductase ◽  
Metabolite Formation ◽  
Isolated Rat Hepatocytes ◽  
Electron Reduction ◽  
Catalyzed Oxidation ◽  
Isolated Rat

Chlorpromazine (CPZ), a member of the largest class of first-generation antipsychotic agents, is known to cause hepatotoxicity in the form of cholestasis and hepatocellular necrosis in some patients. The mechanism of CPZ hepatotoxicity is unclear, but is thought to result from reactive metabolite formation. The goal of this research was to assess potential cytotoxic mechanisms of CPZ using the accelerated cytotoxicity mechanism screening (ACMS) technique with freshly isolated rat hepatocytes. This study identified CPZ cytotoxicity and inhibition of mitochondrial membrane potential (MMP) to be concentration-dependent. Furthermore, inhibition of cytochrome P450s (CYPs), including CYP2D1 and 1A2, delayed CPZ cytotoxicity, suggesting a role for CYP activation of CPZ to a toxic metabolite(s) in this model. Metabolism studies also demonstrated glucuronide and glutathione (GSH) requirement for CPZ detoxification in hepatocytes. Inactivating the 2-electron reduction pathway, NAD(P)H quinone oxidoreductase (NQO1), caused a significant increase in hepatocyte susceptibility to CPZ, indicating quinoneimine contribution to CPZ cytotoxicity. Nontoxic concentrations of peroxidase/H2O2 (inflammatory model) increased cytotoxicity in CPZ-treated hepatocytes and caused additional mitochondrial toxicity. Inflammation further depleted GSH and increased oxidized glutathione (GSSG) levels. Results suggest activation of CPZ to reactive metabolites by 2 pathways in hepatocytes: (i) a CYP-catalyzed quinoneimine pathway, and (ii) a peroxidase-catalyzed oxidation of CPZ to CPZ radicals.

scholarly journals Effect of sublethal preculturing on the survival of probiotics and metabolite formation in set-yoghurt

2015 ◽  
Vol 49 ◽  
pp. 104-115 ◽  
Author(s):  
Sarn Settachaimongkon ◽  
Hein J.F. van Valenberg ◽  
Vera Winata ◽  
Xiaoxi Wang ◽  
M.J. Robert Nout ◽  
...  
Keyword(s):  
Metabolite Formation
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