Carboxylesterases in Drug Metabolism: Challenges and Opportunities

Carboxylesterases (CES) represent an important pathway of drug metabolism. Humans, monkeys, and dogs express two, while rats and mice express up to 16 carboxylesterases. In humans, CES1 is predominately expressed in the liver and CES2 is expressed in the small intestine. The hepatic expression profile in dogs and monkeys is similar to humans. Dogs lack Ces activity in the small intestine. Monkeys, but not humans, express Ces1 in the intestine. Rodents are the only species with plasma carboxylesterase (Ces1c).

This variation in the number and tissue specificity makes interspecies extrapolation a challenge. Several factors including age, genetic polymorphism, and disease state can also affect biotransformation and efficacy of drugs that are metabolized by CES.

Although, there is a low risk of CES-mediated clinical drug-drug interactions (DDI), the potential for such DDI should not be overlooked and should be evaluated. The regulatory guidance documents including the new ICH M12 guidance recommend examining CES-mediated metabolism for drugs that do not undergo significant metabolism by CYP enzymes. CES primarily hydrolyze esters, amides, thioesters, and carbamates. Ester prodrugs are designed to be hydrolyzed to their pharmacologically active metabolite by CES. In addition, novel non-viral drug delivery modalities such as lipid nanoparticles may take advantage of ester hydrolysis for the release of their payload.

This presentation will provide an overview of the current understanding of the role of CES in drug metabolism, factors affecting the expression and activity of CES, tissue distribution, species differences, and potential DDI.

Key concepts discussed in this webinar will include:
Introduction to carboxylesterases
Cellular location, tissue distribution, and species differences
Drug substrate examples
Novel drug delivery modalities utilizing ester hydrolysis
Factors affecting the expression and activity of carboxylesterases
Potential drug-drug interactions
In vitro assays to evaluate drug victim and perpetrator potential associated with carboxylesterases

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About the Presenter: Dr. Brian Ogilvie is the VP of Scientific Consulting at BioIVT where he leads a team that advises clients on in vitro drug-drug interaction studies and program strategy. He received a Ph.D. in toxicology from the University of Kansas Medical Center. He has published various research articles and book chapters, and has been an invited speaker at numerous drug development conferences.