Carboxylesterase 1 Plasma Biomarker for Precision Pharmacotherapy

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Abstract Carboxylesterase 1 (CES1) is the primary hepatic hydrolase, contributing to 80-95% hydrolytic activity in the human liver. CES1 is responsible for the metabolism of many clinically important medication, environmental toxins, and endogenous substances. Hepatic expression and activity of CES1 vary markedly among individuals, which is a major factor contributing to the interindividual variability in response to medications metabolized by CES1. We have identified a loss-of-function CES1 nonsynonymous variant, G143E (rs71647871), and demonstrated that this variant could significantly affect the pharmacokinetics (PK) and pharmacodynamics (PD) of CES1 substrate drugs. However, the G143E variant does not affect CES1 expression and only contributes to a small portion of CES1 function variability because of its low frequency. Therefore, biomarkers capable of predicting CES1 expression are urgently needed to improve the effectiveness and safety of numerous drugs metabolized by CES1. Our preliminary study showed that plasma CES1 protein concentrations were predictive of CES1 in vivo function. Aim 1 of this proposal is to evaluate the correlations between plasma CES1 protein and the PK and PD of the selective CES1 substrate enalapril using the plasma samples collected from an ongoing enalapril PK study (NCT03051282). This enalapril PK study was originally designed to determine the effect of the CES1 variant G143E on enalapril PK and PD in healthy subjects. We expect that combining the plasma CES1 protein biomarker and the CES1 genetic biomarker will explain much of the variability observed in the PK and PD of enalapril. Aim 2 is to determine the correlation between CES1 protein plasma concentrations and hepatic CES1 protein levels in matched plasma and liver tissues. This study will provide mechanistic evidence to support that plasma CES1 protein concentrations are predictive of CES1 protein levels in the liver. We expect that the proposed project will establish plasma CES1 protein as a reliable biomarker for predicting the PK and PD of CES1 substrate drugs. The project is highly impactful because many CES1 substrate drugs have narrow therapeutic indexes, and plasma CES1 protein biomarker-guided precision dosing could significantly improve the efficacy and safety of these medications. The project has the potential to change the paradigm of how to treat patients more effectively by using plasma CES1 protein as a biomarker to optimize therapeutic regimens. This study will also shed light on future research on plasma protein biomarkers for other hepatic drug-metabolizing enzymes.