An Aza-michael Addition Product Causes Incompatibility Between Etacrynic Acid and Theophylline in a Paediatric
S Jirschitzka1, U Girreser2, T Kunze3
1Department of Clinical Pharmacy, Pharmaceutical Institute, Christian-Albrechts-Universität, Kiel, Germany.
Die Pharmazie
|May 16, 2023
Summary
A reaction between etacrynic acid and theophylline was identified in paediatric intensive care units. This drug interaction forms an unknown compound, necessitating separate administration via distinct venous lines.
Area of Science:
- Pharmaceutical Chemistry
- Clinical Pharmacy
- Drug Compatibility Studies
Background:
- Parenteral drugs are frequently administered in paediatric cardiological intensive care units.
- Compatibility studies are essential to ensure patient safety and therapeutic efficacy.
- An unknown reaction product was observed during a compatibility assessment of etacrynic acid and theophylline.
Purpose of the Study:
- To identify the unknown reaction product formed between etacrynic acid and theophylline under intensive care unit conditions.
- To elucidate the chemical structure of the observed adduct.
- To provide recommendations for safe drug administration in clinical practice.
Main Methods:
- High-performance liquid chromatography (HPLC) was used to monitor drug concentrations and detect the reaction product.
- Liquid chromatography-tandem mass spectrometry (LC-MS/MS) confirmed the Michael-like reaction.
- Nuclear magnetic resonance (NMR) spectroscopy (COSY, HSQC, HMBC) was employed for structural elucidation.
Main Results:
- A significant and increasing peak corresponding to a reaction product was observed in HPLC chromatograms.
- Concentrations of both etacrynic acid and theophylline decreased over time.
- The unknown compound was identified as the N-7 substituted adduct: [2-(2,3-dichloro-4-{2-[(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl]butanoyl}phenoxy)acetic acid].
Conclusions:
- Etacrynic acid and theophylline undergo a chemical reaction, forming a distinct adduct.
- This drug interaction is relevant under conditions simulating paediatric intensive care unit administration.
- It is recommended that etacrynic acid and theophylline be administered through separate venous lines to prevent this incompatibility.
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