The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics.

Carboxylesterases (CES) play a critical role in catalyzing hydrolysis of esters, amides, carbamates and thioesters, and bioconverting prodrugs and soft drugs. Human CES1 is one of the most highly expressed drug metabolizing enzymes in the liver, while human intestine only expresses CES2. The unique tissue distribution of CES enzymes provides great opportunities to design prodrugs or soft drugs for tissue targeting. 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. Marked species differences in tissue distribution and catalytic activity have been observed for CES enzymes. Careful evaluation is required when selecting animal models for human translation. Monkeys appear to be more predictive of human pharmacokinetics than other species for CES substrates. In vitro - in vivo extrapolation of clearance is still in its infancy for CES enzymes and further exploration is needed. CES enzymes are moderately inducible through a number of transcription factors and can be repressed by inflammatory cytokines. Low risk of clinical drug-drug interaction is anticipated for CES, although they should not be overlooked, particularly interaction with alcohols. In vitro and in vivo tools are continuously being developed to characterize CES substrates and inhibitors.