Background: Carboxylesterases (CES) play a critical role in catalyzing hydrolysis of esters, amides, carbamates
and thioesters, as well as bioconverting prodrugs and soft drugs. The unique tissue distribution of CES enzymes
provides great opportunities to design prodrugs or soft drugs for tissue targeting. Marked species differences
in CES tissue distribution and catalytic activity are particularly challenging in human translation.
Methods: Review and summarization of CES fundamentals and applications in drug discovery and development.
Results: Human CES1 is one of the most highly expressed drug metabolizing enzymes in the liver, while human
intestine only expresses CES2. CES enzymes have moderate to high inter-individual variability and exhibit low to no
expression in the fetus, but increase substantially during the first few months of life. The CES genes are highly polymorphic
and some CES genetic variants show significant influence on metabolism and clinical outcome of certain
drugs. Monkeys appear to be more predictive of human pharmacokinetics for CES substrates than other species. Low
risk of clinical drug-drug interaction is anticipated for CES, although they should not be overlooked, particularly
interaction with alcohols. CES enzymes are moderately inducible through a number of transcription factors and can
be repressed by inflammatory cytokines.
Conclusion: Although significant advances have been made in our understanding of CESs, in vitro - in vivo extrapolation
of clearance is still in its infancy and further exploration is needed. In vitro and in vivo tools are continuously
being developed to characterize CES substrates and inhibitors.
Keywords: Carboxylesterases, CES1, CES2, prodrugs, soft drugs, tissue distribution, species differences, IVIVE, substrates, inhibitors, drug
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