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

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.