Free radical and drug oxidation products in an intensive care unit sedative: propofol with sulfite.
OBJECTIVE
Some propofol emulsion formulations contain EDTA or sodium metabisulfite to inhibit microbe growth on extrinsic contamination. EDTA is not known to react with propofol formulation components; however, sulfite has been shown to support some oxidation processes and may react with propofol. This study compared the oxidation of propofol and the formation of free radicals by electron paramagnetic resonance analysis in EDTA and sulfite propofol emulsions during a simulated intensive care unit 12-hr intravenous infusion.


METHODS
Controlled laboratory study.


METHODS
University laboratory.


RESULTS
Propofol emulsions (3.5 mL) were dripped from spiked 50-mL vials at each hour for 12 hrs. Two propofol oxidation products, identified as propofol dimer and propofol dimer quinone, were detected in sulfite and EDTA propofol emulsions; however, sulfite propofol emulsion contained higher quantities of both compounds. After initiation of the simulated infusion, the quantities of propofol dimer and propofol dimer quinone increased in the sulfite propofol emulsion, but the lower levels in the EDTA propofol emulsion remained constant. Sulfite propofol emulsion began to visibly yellow at about 6-7 hrs. The EDTA propofol emulsion remained white at all times. The absorbance spectra of the propofol dimer and propofol dimer quinone extracted from sulfite propofol emulsion showed that propofol dimer did not absorb in the visible spectrum, but the propofol dimer quinone had an absorbance peak at 421 nm, causing it to appear yellow. Electron paramagnetic resonance analysis of the propofol emulsion containing metabisulfite revealed that the sulfite propofol emulsion yielded a strong free radical signal consistent with the formation of the sulfite anion radical (SO3*-). The EDTA propofol emulsion yielded no free radical signal above background.


CONCLUSIONS
Sulfite from the metabisulfite additive in propofol emulsion creates an oxidative environment when these emulsions are exposed to air during a simulated intravenous infusion. This oxidation results in propofol dimerization and emulsion yellowing, the latter of which is caused by the formation of propofol dimer quinone. These processes can be attributed to the rapid formation of the reactive sulfite free radical.
Baker
Max T
MT
Department of Anesthesia, University of Iowa, Iowa City, USA.
Gregerson
Marc S
MS
Martin
Sean M
SM
Buettner
Garry R
GR
D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D003422:Critical Care / Q000379:methods; D019281:Dimerization; D004340:Drug Contamination / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D004492:Edetic Acid / Q000737:chemistry* / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D004655:Emulsions; D005609:Free Radicals / Q000032:analysis*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D015742:Propofol / Q000737:chemistry* / Q000378:metabolism; D011809:Quinones / Q000032:analysis / Q000378:metabolism; D013447:Sulfites / Q000737:chemistry* / Q000378:metabolism; D013997:Time Factors
D004655:Emulsions; D005609:Free Radicals; D006993:Hypnotics and Sedatives; D011809:Quinones; D013447:Sulfites; C030981:metabisulfite; D004492:Edetic Acid; D015742:Propofol