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Free Radical and Drug Oxidation Products in an Intensive Care Unit Sedative: Propofol with Sulfite*

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Free Radical and Drug Oxidation Products in an Intensive Care Unit Sedative: Propofol with Sulfite* Free radical and drug oxidation products in an intensive care unit sedative: Propofol with sulfite* Max T. Baker, PhD; Marc S. Gregerson, BS; Sean M. Martin, BA; Garry R. Buettner, PhD Objectives: Some propofol emulsion formulations contain EDTA The EDTA propofol emulsion remained white at all times. The or sodium metabisulfite to inhibit microbe growth on extrinsic absorbance spectra of the propofol dimer and propofol dimer contamination. EDTA is not known to react with propofol formu- quinone extracted from sulfite propofol emulsion showed that lation components; however, sulfite has been shown to support propofol dimer did not absorb in the visible spectrum, but the some oxidation processes and may react with propofol. This study propofol dimer quinone had an absorbance peak at 421 nm, compared the oxidation of propofol and the formation of free causing it to appear yellow. Electron paramagnetic resonance radicals by electron paramagnetic resonance analysis in EDTA analysis of the propofol emulsion containing metabisulfite and sulfite propofol emulsions during a simulated intensive care revealed that the sulfite propofol emulsion yielded a strong unit 12-hr intravenous infusion. free radical signal consistent with the formation of the sulfite ⅐؊ Design: Controlled laboratory study. anion radical (SO3 ). The EDTA propofol emulsion yielded no free Setting: University laboratory. radical signal above background. Measurements and Main Results: Propofol emulsions (3.5 mL) Conclusion: Sulfite from the metabisulfite additive in propofol were dripped from spiked 50-mL vials at each hour for 12 hrs. emulsion creates an oxidative environment when these emul- Two propofol oxidation products, identified as propofol dimer and sions are exposed to air during a simulated intravenous infu- propofol dimer quinone, were detected in sulfite and EDTA propo- sion. This oxidation results in propofol dimerization and emul- fol emulsions; however, sulfite propofol emulsion contained sion yellowing, the latter of which is caused by the formation higher quantities of both compounds. After initiation of the sim- of propofol dimer quinone. These processes can be attributed ulated infusion, the quantities of propofol dimer and propofol to the rapid formation of the reactive sulfite free radical. (Crit dimer quinone increased in the sulfite propofol emulsion, but the Care Med 2003; 31:787–792) lower levels in the EDTA propofol emulsion remained constant. KEY WORDS: sulfite; propofol; metabisulfite; propofol oxidation; Sulfite propofol emulsion began to visibly yellow at about 6–7 hrs. free radicals; EDTA; propofol dimer; propofol dimer quinone ropofol (2,6-diisopropylphe- lations are oil-in-H2O emulsions consist- analysis of the sulfite propofol emulsion nol) is an intravenous sedative ing of propofol (1%, 10 mg/mL), soybean and propofol emulsion containing EDTA that is administered continu- oil (100 mg/mL), egg yolk lecithin (12 (EDTA propofol emulsion) showed that ously to a wide variety of crit- mg/mL), and glycerol (22.5 mg/mL) in the sulfite propofol emulsion, but not the Pically ill patients, including those having H2O (1). Because these emulsions can EDTA propofol emulsion, contained vari- coronary artery bypass grafts, adult respi- support the growth of bacteria and yeast able quantities of the lipid peroxidation ratory distress syndrome, asthma, head when extrinsically contaminated (2), an product, malondialdehyde, which in- trauma, status epilepticus, pneumonia, agent to retard the growth of microor- creased over time after air exposure (11). and sepsis (according to manufacturer ganisms is deemed necessary. Sodium Propofol dimer is a product of a one- prescribing information from Astra- metabisulfite (Na2S2O5, 0.25 mg/mL) (3, electron oxidation of propofol to form Zeneca Pharmaceuticals and Gensia Sicor 4) or EDTA (0.05 mg/mL) (5) are added to propofol radicals that couple with one Pharmaceuticals). Propofol is insoluble some propofol emulsions for that pur- another, generating the dimer product in aqueous media (propofol octanol/H2O pose. (6). Lipid peroxidation is a free radical ϭ partition coefficient 6800:1) and there- Drug additives are usually considered process involving the formation of lipid fore is formulated in a lipid-based vehicle. inactive formulation components; how- radicals in the presence of oxygen (12). It The current commercial propofol formu- ever, there is evidence that sulfite is re- is proposed that these sulfite-promoted sponsible for promoting the oxidation of chemical processes are initiated by the propofol and lipids in emulsions. For ex- formation of sulfite-derived radicals. *See also p. 981. ample, when propofol emulsions contain- The precise conditions for sulfite- From the Department of Anesthesia (MTB, MSG), ing metabisulfite (sulfite propofol emul- supported oxidation of propofol in sulfite ESR Facility (SMM), and Free Radical and Radiation sion) are exposed to air, a propofol propofol emulsions remain unclear. Fur- Biology (GRB), University of Iowa, Iowa City, IA. Supported, in part, by AstraZeneca Pharmaceuti- dimerized product appears (6). A yellow thermore, the detection of free radicals in cals LP, Wilmington, DE. coloration is also sometimes noted after emulsions of propofol has not been exam- Copyright © 2003 by Lippincott Williams & Wilkins exposure of the sulfite propofol emulsion ined. Twelve hours is the recommended DOI: 10.1097/01.CCM.0000053560.05156.73 to air (7–10). In addition, a comparative hang time for propofol emulsion in in- Crit Care Med 2003 Vol. 31, No. 3 787 mins and an isocratic period of 100% metha- nol for 4 mins. A sample size of 5 ␮L was injected, and fractions in the eluate were scanned from 200 to 500 nm. The data were collected using the Xcalibur Software system (Herndon, VA). Propofol dimer was quanti- tated by its absorbance at 266 nm and propofol dimer quinone by its absorbance at 421 nm. Standard curves were constructed using stan- dard propofol dimer and propofol dimer qui- none. Electron Paramagnetic Resonance Spec- troscopy. Electron paramagnetic resonance (EPR) spectra were recorded with a Bruker EMX EPR spectrometer (Bruker Instruments, Billerica, MA) at room temperature. Samples were prepared by adding 5,5-dimethyl-1- pyrroline-N-oxide (DMPO, final concentration of 25 mM) to the propofol emulsions (total volume of 0.5 mL) from commercially sup- plied vials. EPR spectra were collected imme- diately after sample preparation. The emul- sions were maintained at room temperature at all times. All spectra were collected using identical conditions: each represents the sig- nal-averaged result of five scans; scan rate, 80 G/84 s; microwave power, 40 mW with a TM cavity and 10 mm flat cell; frequency, 9.77 GHz; modulation amplitude, 1.00 G; time con- stant, 82 ms. Figure 1. Liquid chromatography/mass spectral (MS) of propofol dimer quinone and secondary Values are reported as mean of duplicate or fragmentation (MS/MS) of the mass-to-change ratio (m/z) 353 ion. triplicate determinations (ϮSD). Statistics were performed by analysis of variance re- peated measures (Scheffe’s F test). p Values of Յ tensive care unit sedation, after which it out and collected for analysis. At each hour for .05 were considered significant. is recommended that the emulsion be up to 12 hrs, an additional 3.5-mL aliquot was discarded after vial spiking. The present released, collected, and analyzed. RESULTS study compared propofol degradation and Propofol Product Analysis. One milliliter ␮ free radical formation in EDTA and sulfite of collected emulsion was treated with 100 L High-pressure liquid chromatography propofol emulsions during a simulated of a 10% NaCl solution to crack the emulsion. analysis of ethyl acetate extracts of propo- intensive care unit 12-hr intravenous in- Ethyl acetate (1 mL) was added to the 1-mL fol emulsions revealed the presence of cracked emulsion, and the mixture was vigor- fusion in the laboratory. two major fractions that could be identi- ously shaken, followed by centrifugation to fied as propofol oxidation products. The ␮ separate the phases. Approximately 100 Lof first fraction chromatographed at approx- MATERIALS AND METHODS the ethyl acetate phase was taken for liquid imately 6.3–6.5 mins in the system used chromatography/mass spectral analysis. Chemicals. Fifty-milliliter vials of EDTA Liquid Chromatography/Mass Spectral and was identified as propofol dimer. The propofol emulsion and authentic propofol Analysis of Propofol Products. The ethyl ace- absorbance spectrum from 200 to 500 nm dimer and propofol dimer quinone were ob- tate extracts from propofol emulsions were of this peak showed an absorbance peak tained from AstraZeneca Pharmaceuticals analyzed on a Surveyor liquid chromatogra- at 266 nm and no absorbance in the vis- (Wilmington, DE). The propofol dimer and ible range. This compound chromato- propofol dimer quinone standards had purities phy/mass spectral analysis system (LCQDeca of Ͼ97%. Propofol emulsion containing met- MS system, ThermoFinnigan, San Jose, CA) graphed identically with authentic propo- abisulfite, also in 50-mL vials, was purchased having a photodiode array detector linked in fol dimer, and it exhibited the same from Gensia Sicor Pharmaceuticals (Irvine, series to the mass spectrum detector. The absorbance spectrum as authentic propo- CA). mass spectrum detector utilized atmospheric fol dimer, confirming that the propofol Simulated Intravenous Infusion. Vials of pressure chemical ionization and a normal- dimer is a visibly colorless compound. propofol emulsion were dripped by inserting a ized collision energy of 40%. This instrument The electrospray mass spectrum of the Flu-Vent vented spike and tubing (Flu Ven was equipped with a Discovery HS C-18 MS ϫ ␮ propofol dimer confirms the presence of 0153-C, Venusa, El Paso, TX) into intact, prop- analytical column (75 2.1 mm ID, 3 m) propofol dimer in these propofol emul- fitted with a guard column. Propofol and erly stored, commercially supplied vials of sions. Propofol dimer (molecular weight propofol product separation involved the use propofol emulsion. The vials were inverted ϭ 354 Da) poorly ionizes in electrospray, and hung on a ringstand at room temperature of a mobile phase gradient system.
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