A Novel Tertiary Carbamate Prodrug Strategy to Overcome Metabolic Barriers in Oral Ketamine Delivery.
ChemMedChem January 1, 2026 Juulia Järvinen, Santosh Kumar Adla, Janne Tampio et al.
A ketamine prodrug designed with a tyrosine methyl ester and a tertiary carbamate linker aimed to improve oral absorption and reduce abuse potential. The prodrug showed moderate solubility and stability at physiological pH but did not release ketamine in enzyme-containing media. In mice, oral administration led to rapid metabolic conversion but only low levels of ketamine in plasma, liver, and brain, resulting in very low oral bioavailability. The design does not sufficiently promote ketamine release or systemic exposure, indicating that further structural optimization is needed for therapeutically meaningful delivery.