A Novel Tertiary Carbamate Prodrug Strategy to Overcome Metabolic Barriers in Oral Ketamine Delivery.
Juulia Järvinen, Santosh Kumar Adla, Janne Tampio, Aaro J. Jalkanen, Kenneth B Sloan, Kristiina M Huttunen, Jarkko Rautio
ChemMedChem 2026 DOI: 10.1002/cmdc.202500856 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vivo pharmacokinetic study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | ketamine prodrug conjugated to tyrosine methyl ester |
| Topics | Ketamine Esketamine |
| Keywords | Bioavailability Oral administration Pharmacokinetics Prodrug |
| Key points | The tertiary carbamate-based ketamine prodrug showed limited ketamine release and very low oral bioavailability in mice, indicating insufficient systemic exposure. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 10
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) CNS Neuroscience & Therapeutics April 10, 2013
- Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes Pain August 1, 1999
and 5 more in the library