Regulation of carboxylesterases and its impact on pharmacokinetics and pharmacodynamics: an up-to-date review

ABSTRACT

Introduction

Carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) are among the most abundant hydrolases in humans, catalyzing the metabolism of numerous clinically important medications, such as methylphenidate and clopidogrel. The large interindividual variability in the expression and activity of CES1 and CES2 affects the pharmacokinetics (PK) and pharmacodynamics (PD) of substrate drugs.

Areas covered

This review provides an up-to-date overview of CES expression and activity regulations and examines their impact on the PK and PD of CES substrate drugs. The literature search was conducted on PubMed from inception to January 2024.

Expert opinion

Current research revealed modest associations of CES genetic polymorphisms with drug exposure and response. Beyond genomic polymorphisms, transcriptional and posttranslational regulations can also significantly affect CES expression and activity and consequently alter PK and PD. Recent advances in plasma biomarkers of drug-metabolizing enzymes encourage the research of plasma protein and metabolite biomarkers for CES1 and CES2, which could lead to the establishment of precision pharmacotherapy regimens for drugs metabolized by CESs. Moreover, our understanding of tissue-specific expression and substrate selectivity of CES1 and CES2 has shed light on improving the design of CES1- and CES2-activated prodrugs.

KEYWORDS:

• Carboxylesterase
• CES1
• CES2
• drug metabolism
• environmental regulators
• genetic polymorphisms
• pharmacokinetics
• pharmacodynamics

Article highlights

• Genetic polymorphisms in CES1 and CES2 have shown a modest impact on drug exposure and response.

• The CES1 rs71647871 variant, the most studied loss-of-function variant, consistently and significantly affects the PK and PD of CES1 substrate drugs.

• The clinical significance of other genetic variants is debatable, presumably due to their small effect size.

• Regulation beyond genetic polymorphisms, such as age, gender, inducers, and inhibitors, could further explain the variability in CES functionality, PK, and PD.

• CES1 and CES2 in plasma and EVs have the potential to be established as biomarkers for precision pharmacotherapy of CES substrate drugs.

• A better understanding of tissue-specific expression and substrate selectivity of CES1 and CES2 could shed light on improving the design of prodrugs.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425255.2024.2348491

Additional information

Funding

This manuscript was funded by the National Institute of General Medical Sciences [Grant R01GM144401].