Journal ArticleDOI
Esterase Activities in the Blood, Liver and Intestine of Several Preclinical Species and Humans
TLDR
Substantial species differences in activity of these esterases were observed between the mouse, rat, dog monkey and human, and such species differences must be considered when using these preclinical species to optimize the pharmacokinetic properties of ester compounds intended for human use.Abstract:
Species and tissue differences in the activity of three major classes of esterases, carboxylesterase (CE), butyrylcholinesterase (BChE) and paraoxonase (PON), were studied. Substantial species differences in activity of these esterases were observed between the mouse, rat, dog monkey and human. Such species differences must be considered when using these preclinical species to optimize the pharmacokinetic properties of ester compounds intended for human use.read more
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Predicting human exposure of active drug after oral prodrug administration, using a joined in vitro/in silico-in vivo extrapolation and physiologically-based pharmacokinetic modeling approach.
Jonas Malmborg,Bart Ploeger +1 more
TL;DR: Adding quantitative information about prodrug conversion in the gut, liver and blood to a PBPK model for the absorption, distribution, metabolism and excretion properties of prodrugs and their active moieties resulted, retrospectively, in reasonable predictions of the human PK when the ADME properties are well understood.
Journal ArticleDOI
Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans.
TL;DR: This study is the first to determine that human arylacetamide deacetylase (AADAC) is involved in 2-oxo-clopidogrel production from vicagrel in human intestine, and deepens the understanding of the bioactivation and metabolism properties of vicag Rel in humans.
Hyperpolarized 1,3-13C2-Ethyl acetoacetate is a novel diagnostic metabolic marker of liver cancer
Pernille Rose Jensen,Sonia Colombo,Luigi Miragoli,Magnus Karlsson,Claudia Cabella,Luca Venturi,Fabio Tedoldi,Mathilde H. Lerche +7 more
TL;DR: Low molecular weight ethyl‐esters were identified, which showed high specificity for carboxyl esterases and proved in many cases to possess good properties for signal enhancement, and hyperpolarized [1,3‐13C2]ethyl acetoacetate (EAA) was shown to provide a metabolic fingerprint of HCC.
Journal ArticleDOI
Interspecies differences in stability kinetics and plasma esterases involved in hydrolytic activation of curcumin diethyl disuccinate, a prodrug of curcumin
Pahweenvaj Ratnatilaka Na Bhuket,Ponsiree Jithavech,Boonsri Ongpipattanakul,Pornchai Rojsitthisak +3 more
TL;DR: The difference in the hydrolysis rates and the metabolizing enzymes of CDD metabolism in rat, dog and human plasma observed here is of benefit to further in vivo studies and provides a rationale for designing ester prodrugs of CUR with esterase-specific bioactivation.
Journal ArticleDOI
Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat intestine: in vitro, in situ intestinal perfusion and portal vein cannulation models
Vinay K. Holenarsipur,Nilesh Gaud,Jaydeep Sinha,Sankara Sivaprasad,Priyadeep Bhutani,Murali Subramanian,Sheelendra Pratap Singh,Rambabu Arla,Sundeep Paruchury,Tarun Sharma,Punit Marathe,Sandhya Mandlekar +11 more
TL;DR: It was demonstrated that even though enalapril has been shown to be a specific substrate for CES1, it is converted to enalAPrilat to a significant extent in the intestine.