Title:The Metabolism of the New Benzodiazepine Remimazolam
Volume: 25
Issue: 2
Author(s): Wolfgang Schmalix, Karl-Uwe Petersen, Marija Pesic and Thomas Stöhr*
Affiliation:
- Department of R&D. Paion GmbH, Heussstrasse 25, 52078, Aachen, Germany
Keywords:
Remimazolam, metabolism, CNS7054, carboxylesterases, sedation, anaesthesia.
Abstract:
Background: Remimazolam (RMZ) is a novel ultrashort-acting benzodiazepine used for sedation
by intravenous administration. The pharmacophore of RMZ includes a carboxyl ester group sensitive to esterase-
mediated hydrolysis, which is the primary path of metabolic elimination. However, for the sake of drug
safety, a deeper and broader knowledge of the involved metabolic pathways and the evolving metabolites is required.
Information is needed on both humans and experimental animals to evaluate the possibility that humans
form harmful metabolites not encountered in animal toxicity studies.
Objective: The current study aimed at identifying the mechanisms of remimazolam's metabolism and any potential
clinically significant metabolites.
Methods: Using tissue homogenates from various animals and humans, the liver was identified as the tissue
primarily responsible for the elimination of RMZ. CNS7054, the hydrolysis product of remimazolam, was
identified as the only clinically relevant metabolite. Using bacterial or eukaryotic over-expression systems, carboxylesterase
1 (CES1) was identified as the iso-enzyme predominantly involved in RMZ metabolism, with
no role for carboxylesterase 2. Using a variety of inhibitors of other esterases, the contribution to elimination
mediated by esterases other than CES1 was excluded.
Results: Besides tissue carboxylesterases, rodents expressed an RMZ esterase in plasma, which was not present
in this compartment in other laboratory animals and humans, hampering direct comparisons. Other pathways
of metabolic elimination, such as oxidation and glucuronidation, also occurred, but their contribution to
overall elimination was minimal.
Conclusion: Besides the pharmacologically non-active metabolite CNS7054, no other clinically significant
metabolite of remimazolam could be identified.
