# A Novel Tertiary Carbamate Prodrug Strategy to Overcome Metabolic Barriers in Oral Ketamine Delivery

## TL;DR

Researchers designed a new prodrug of ketamine to improve its oral delivery and reduce abuse potential, but found it had limited effectiveness.

## Contribution

A novel tertiary carbamate prodrug strategy was developed to enhance oral ketamine delivery and reduce abuse risk.

## Key findings

- The prodrug showed good chemical stability but limited ketamine release in vitro.
- In vivo studies showed low ketamine levels in plasma, liver, and brain after oral administration.
- Structural optimization is needed to improve bioavailability and therapeutic delivery.

## Abstract

Ketamine, a rapid‐acting N‐methyl‐D‐aspartate (NMDA) receptor antagonist, has therapeutic potential beyond anesthesia, including treatment‐resistant depression. However, its low oral bioavailability due to extensive first‐pass metabolism and high abuse potential limit outpatient use. This study describes the design, synthesis, and in vivo evaluation of a ketamine prodrug conjugated to tyrosine methyl ester via a hydrolytically sensitive tertiary carbamate linker to improve oral absorption, achieve sustained release, and reduce abuse risk. The prodrug displayed moderate aqueous solubility and good chemical stability at physiological pH but was rapidly metabolized in enzyme‐containing media via demethylation of the tyrosine methyl ester to a demethylated prodrug, with no detectable ketamine release in vitro. In vivo pharmacokinetic studies in mice demonstrated that the prodrug underwent rapid metabolic conversion, resulting in detectable, though low, levels of released ketamine in plasma, liver, and brain. However, ketamine release was limited, and oral administration yielded very low bioavailability. These findings indicate that while tertiary carbamate‐based prodrugs can undergo in vivo activation, the current design does not sufficiently promote ketamine release or systemic exposure. Further structural optimization is required to improve oral bioavailability and achieve therapeutically meaningful delivery of ketamine.

This study describes the development of an orally optimized ketamine prodrug designed to improve pharmacokinetic properties, extend therapeutic efficacy, and minimize adverse effects and abuse liability.© 2026 WILEY‐VCH GmbH