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Volume 25, Issue 6
  • ISSN: 1389-2002
  • E-ISSN: 1875-5453

Abstract

Background

The ultra-short-acting benzodiazepine remimazolam, approved for procedural sedation and general anesthesia, is inactivated by carboxylesterase 1 (CES1).

Objective

Remimazolam´s involvement in CES1-mediated drug-drug interactions (DDIs) was investigated.

Methods

Possible interactions of remimazolam were studied in co-exposure experiments with eleven different drugs. Further, substrates and inhibitors of CES1, identified in the literature, were evaluated for possible inhibition using pharmacokinetic and Ki or IC values. Compounds with only one published inhibitory concentration and CES1 substrates lacking inhibition data were assigned conservative Ki values.

Results

In human liver homogenates and/or blood cells, remimazolam showed no significant inhibition of esmolol and landiolol metabolism, which, in turn, at up to 98 and 169 µM, respectively, did not inhibit remimazolam hydrolysis by human liver homogenates. In human liver S9 fractions, IC values ranged from 0.69 µM (simvastatin) and 57 µM (diltiazem) to > 100 µM (atorvastatin) and, for the remaining test items (bupropion, carvedilol, nelfinavir, nitrendipine, and telmisartan), they ranged from 126 to 658 µM. Remifentanil was ineffective even at 1250 µM. Guidance-conforming evaluation revealed no relevant drug-drug interactions with remimazolam CES1. The algorithm-based predictions were consistent with human study data. Among CES1 inhibitors and substrates identified in the literature, only dapsone and rufinamide were found to be possible inhibitors of remimazolam metabolism.

Conclusion

Data and analyses suggest a very low potential of remimazolam for pharmacokinetic DDIs mediated by CES1. The theoretical approach and compiled data are not specific to remimazolam and, hence, applicable in the evaluation of other CES1 substrates.

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Carboxylesterase 1-Based Drug-Drug Interaction Potential of Remimazolam: In-Vitro Studies and Literature Review
Current Drug Metabolism 25, 431 (2024); https://doi.org/10.2174/0113892002308233240801104910
/content/journals/cdm/10.2174/0113892002308233240801104910
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  • Article Type:     Research Article
Keyword(s): Carboxylesterase 1; CES1 inhibition; cytochrome P450; DMES; drug-drug interactions; remimazolam

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