Determination of perfluorobutane in rat blood by automatic headspace capillary gas chromatography and selected ion monitoring mass spectrometry
Introduction
SonazoidTM (NC100100) is a new ultrasound contrast agent under development for indications such as left ventricular border enhancement, myocardial perfusion mapping, detection of focal lesions in the liver and several vascular applications such as characterisation of the vascularity of tumours [1]. The contrast agent is a lipid-stabilised suspension of perfluorobutane (PFB) gas microbubbles with a median volume diameter of 2.4–3.5 μm.
The perfluorocarbons have structures analogous to the familiar hydrocarbons but possess very different chemical and physical properties. Perfluorocarbons are normally much less reactive than hydrocarbons towards all chemical reagents except alkali metals. Temperatures approaching 1000°C are required to decompose perfluoroethane and perfluoropropane, but even though perfluorocarbons of higher molecular weights are thermally less stable, most perfluorocarbons are stable below 300°C. Completely fluorinated alkanes are essentially non-toxic [2]. Perfluorocarbon liquids have thus been used in vitreoretinal surgery as an instrument for manipulating intraocular tissues [3], [4] and selected perfluorocarbons have been used as tracers for monitoring the movement of the atmosphere [5], [6], [7] and in reservoir studies [8].
Gas chromatography (GC) has been the preferred analytical technique for the determination of perfluorocarbons. One of the requirements for separating volatile compounds is the use of a stationary phase that provides sufficient retention for the compounds to be measured. With the introduction of chemically bonded phases on capillary columns, selectivity could be combined with a high theoretical plate number. Adsorption materials such as Al2O3 and porous polymer types of materials in porous layer open tubular (PLOT) capillary columns have been found to be effective for analyses of several fluorocarbons [9], [10]. Perfluorocarbon compounds have been analysed with alumina PLOT [11], fused-silica SE-30 [12], fused-silica SE-54 [13] and fused-silica DB-Petro 100 [14] capillary columns. The perfluorocarbons have been detected with high sensitivity by electron-capture detection [12], [14], [15], [16] or electron-capture negative ion chemical ionisation mass spectrometry (MS) [13]. GC–MS with electron impact (EI) ionisation has been extensively used for determination of aerosol propellant fluorocarbons in biological tissues [17], [18], [19], [20], [21].
To determine the pharmacokinetic properties of the new contrast agent, SonazoidTM, in animals, we developed an automatic headspace sampler capillary GC–EI–MS method for specific determination of PFB in rat blood. The method was validated and the validation results are presented in this paper.
Section snippets
Materials
PFB, C4F10, was purchased from 3M Speciality Chemicals Division, USA, or from F2 Chemicals Ltd., England. Fluorotrichloromethane (CFC 11) >99% was from Sigma-Aldrich, England. Perfluoropropane, perfluoropentane and perfluorohexane were from Fluorochem, England. SonazoidTM was from Nycomed Imaging AS, Norway. Ethanol (96%) was spiritus fortis and 2-propanol was analytical grade. Sodium chloride (NaCl), 9 mg/ml, was purchased from Kabi Pharmacia AB, Sweden. Heparinised blood was collected from
Results and discussion
The main purpose of this study was to develop a method for the determination of PFB in rat blood after i.v. injection of the ultrasound contrast agent SonazoidTM. Since PFB is a highly volatile substance, headspace injection using an automatic headspace sampler coupled with GC–MS was the method of choice. Fig. 1 shows that PFB was chromatographically separated from some of the closely related perfluorocarbons. CFC 11 was chosen as the internal standard of the method and Fig. 2 shows the EI+
Acknowledgements
We thank Per Christian Sontum for the work with obtaining the Coulter data.
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Direct Emulsification of Stable Superheated Perfluorobutane Nanodroplets by Sonication: Addressing the Limitations of the Microbubble Condensation Technique
2024, Ultrasound in Medicine and BiologyRecent advances in ultrasound-based diagnosis and therapy with micro- and nanometer-sized formulations
2017, MethodsCitation Excerpt :The size of MB mostly ranges between 1 and 8 μm in diameter and they were initially filled with air [19]. In second-generation formulations, the air was replaced by low-soluble gasses like perfluorocarbons (PFC) (perfluoropropane [20] or perfluorobutane [21]) or sulfur hexafluoride [22] in order to increase the stability of the structure, since nitrogen and oxygen diffuse rapidly out of the gas core. MB are usually surrounded by a phospholipid, protein or biodegradable polymeric shell structure to stabilize the formulation further and narrow their size distribution (Fig. 1) [23].
Blood monitoring of perfluorocarbon compounds (F-tert-butylcyclohexane, perfluoromethyldecalin and perfluorodecalin) by headspace-gas chromatography-tandem mass spectrometry
2015, TalantaCitation Excerpt :Nevertheless, despite their relatively high molecular weight, PFCs constitute volatile compounds. Therefore, headspace extractions have rapidly become the technique of choice for these molecules and have reduced the time of extraction and analysis, increasing the operator safety through the automisation of the device [28–31]. Since the early 2000’s, Solid-Phase Microextraction (SPME) constitutes an efficient tool for this kind of extraction.
Pharmacokinetics of Perfluorobutane Following Intravenous Bolus Injection and Continuous Infusion of Sonazoid™ in Healthy Volunteers and in Patients with Reduced Pulmonary Diffusing Capacity
2008, Ultrasound in Medicine and BiologyCitation Excerpt :An electron microscopy study showed that it is the Kupffer cells, i.e., the macrophages located in the liver sinusoids, which are responsible for the liver uptake of the microbubbles; no liver uptake of microbubbles was observed by parenchymal, stellate or endothelial cells (Kindberg et al. 2003). Gas chromatography coupled to mass spectrometry (GC-MS) is the preferred analytical technique for determination of perfluorocarbons and we have previously described validated methods for analysis of PFB in rat blood (Hvattum et al. 2001), exhaled air from rats (Uran et al. 2005) and rat tissues (Toft et al. 2006). In the present work, we used modifications of these methods to determine the pharmacokinetics of PFB in human blood and exhaled air.
Disposition of perfluorobutane in rats after intravenous injection of Sonazoid™
2006, Ultrasound in Medicine and BiologyA respiration-metabolism chamber system and a GC-MS method developed for studying exhalation of perfluorobutane in rats after intravenous injection of the ultrasound contrast agent Sonazoid™
2005, Journal of Pharmaceutical and Biomedical Analysis
- 1
Present address: Department of Chemistry and Biotechnology, Agricultural University of Norway, N-1432 Ås, Norway.
- 2
Present address: National Institute of Forensic Toxicology, PO Box 495, Sentrum, N-0105 Oslo, Norway.