# Carboxylesterase 1 Plasma Biomarker for Precision Pharmacotherapy

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $312,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10908576
- **Project number:** 5R01GM144401-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Haojie Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $312,000
- **Award type:** 5
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908576

## Citation

> US National Institutes of Health, RePORTER application 10908576, Carboxylesterase 1 Plasma Biomarker for Precision Pharmacotherapy (5R01GM144401-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10908576. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*