Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators

Abstract

Carboxylesterase (CES) 1 is the most abundant drug-metabolizing enzyme in human livers, comprising approximately 1% of the entire liver proteome. CES1 is responsible for 80%-95% of total hydrolytic activity in the liver and plays a crucial role in the metabolism of a wide range of drugs (especially ester-prodrugs), pesticides, environmental pollutants, and endogenous compounds. Expression and activity of CES1 vary markedly among individuals, which is a major contributing factor to interindividual variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by CES1. Both genetic and nongenetic factors contribute to CES1 variability. Here, we discuss genetic polymorphisms, including single-nucleotide polymorphisms (SNPs), and copy number variants and nongenetic contributors, such as developmental status, genders, and drug-drug interactions, that could influence CES1 functionality and the PK and PD of CES1 substrates. Currently, the loss-of-function SNP G143E (rs71647871) is the only clinically significant CES1 variant identified to date, and alcohol is the only potent CES1 inhibitor that could alter the therapeutic outcomes of CES1 substrate medications. However, G143E and alcohol can only explain a small portion of the interindividual variability in the CES1 function. A better understanding of the regulation of CES1 expression and activity and identification of biomarkers for CES1 function in vivo could lead to the development of a precision pharmacotherapy strategy to improve the efficacy and safety of many CES1 substrate drugs. SIGNIFICANCE STATEMENT: The clinical relevance of CES1 has been well demonstrated in various clinical trials. Genetic and nongenetic regulators can affect CES1 expression and activity, resulting in the alteration of the metabolism and clinical outcome of CES1 substrate drugs, such as methylphenidate and clopidogrel. Predicting the hepatic CES1 function can provide clinical guidance to optimize pharmacotherapy of numerous medications metabolized by CES1.

Fig. 1.

CES1 gene structure and haplotypes. CES1 gene consists of 14 exons located on chromosome 16q13-q22.1, and CES1P1 is a pseudogene, lying tail-to-tail with CES1. CES1, CES1P1, and their variants CES1 VAR and CES1P1 VAR form four major haplotypes. Red represents where stop codon is located. Transcription efficiency of CES1P1 VAR is approximately 2% of CES1.

Fig. 2.

D-methylphenidate comes as a single active ingredient (Focalin) or in combination with l-methylphenidate (racemic mixture) (Ritalin). D-methylphenidate is approximately 10 times more pharmacologically potent than l-methylphenidate, whereas l-methylphenidate is a better CES1 substrate. Ethylphenidate can be formed via transesterification with ethanol.

Fig. 3.

Clopidogrel metabolic pathway. Clopidogrel is a non-ester-prodrug that needs to be activated by two oxidation reactions via CYPs. Clopidogrel and its intermediate and active metabolites are all metabolized (deactivated) by CES1.

Fig. 4.

ACE inhibitors (enalapril and trandolapril) metabolism. Enalapril and trandolapril are ester-prodrugs that need to be activated by CES1.

Fig. 5.

Dabigatran metabolic pathway. Dabigatran is a prodrug that activated by both CES1 and CES2.