Systemic Metabolic Alterations Induced by Etodolac in Healthy Individuals

Area of Science:

• Pharmacology
• Metabolomics
• Drug Metabolism

Background:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) like Etodolac can have systemic effects beyond their primary targets.
• Understanding the broader metabolic impact of NSAIDs is crucial for comprehensive drug evaluation.
• Untargeted metabolomics offers a powerful approach to identify drug-induced metabolic changes.

Purpose of the Study:

• To investigate the metabolic impact of a single oral dose of Etodolac in healthy male volunteers using untargeted metabolomics.
• To identify endogenous metabolites influenced by Etodolac plasma levels.
• To explore potential therapeutic pathways and off-target effects of Etodolac.

Main Methods:

• Thirty healthy participants received a 400 mg dose of Etodolac.
• Serial plasma samples were collected and analyzed using LC/MS-based untargeted metabolomics.
• Pharmacokinetic analysis was performed alongside metabolomic profiling.

Main Results:

• A single dose of Etodolac significantly dysregulated 997 metabolites.
• Eighty human endogenous metabolites were identified as being influenced by Etodolac.
• Seventeen metabolites showed time-dependent changes aligned with Etodolac pharmacokinetics, while 27 displayed inverse trends.

Conclusions:

• Etodolac influences critical metabolic pathways, including arachidonic acid, sphingolipid metabolism, and unsaturated fatty acid biosynthesis.
• These metabolic alterations may complement Etodolac's COX-2 inhibition and contribute to its anti-inflammatory properties.
• The study provides novel insights into Etodolac's metabolic effects in healthy individuals, potentially guiding future therapeutic strategies.