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A simplified method for therapeutic drug monitoring of mitotane by gas chromatography-electron ionization-mass spectrometry.

ABSTRACT: Mitotane is a key drug for the treatment of adrenal cortical carcinoma. Due to its narrow therapeutic window, 14-20 μg/mL, monitoring its concentration is crucially important. In this study, a simplified method for measuring mitotane in plasma using gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) was developed. Through deproteination and liquid-liquid extraction, mitotane and an internal standard (IS) were extracted from plasma samples. GC-EI-MS yielded retention times of 8.2 and 8.7 min, for mitotane and the IS, respectively, with a total run time of 12 min. Selectivity and intra-/inter-batch accuracy and precision analyses provided a lower limit of quantification of 0.25 μg/mL, and a calibration curve between 0.25 and 40 μg/mL had good linearity (coefficient of determination = 0.992). The matrix effect factor and percent recovery of the method had good precision. Additionally, long-term sample stability was observed below 4°C. In a clinical setting, mitotane levels in plasma from an adrenal cortical carcinoma patient were within calibration range. Therefore, this simplified method can be applied to routine therapeutic drug monitoring of mitotane, which may contribute to improved treatment of adrenal cortical carcinoma.

SUBMITTER: Ando M

PROVIDER: S-EPMC7064981 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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A simplified method for therapeutic drug monitoring of mitotane by gas chromatography-electron ionization-mass spectrometry.

Ando Motozumi M Hirabatake Masaki M Yasui Hisateru H Fukushima Shoji S Sugioka Nobuyuki N Hashida Tohru T

Biomedical chromatography : BMC 20200128 3

Mitotane is a key drug for the treatment of adrenal cortical carcinoma. Due to its narrow therapeutic window, 14-20 μg/mL, monitoring its concentration is crucially important. In this study, a simplified method for measuring mitotane in plasma using gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) was developed. Through deproteination and liquid-liquid extraction, mitotane and an internal standard (IS) were extracted from plasma samples. GC-EI-MS yielded retention times of 8.2 ...[more]

PMID: 31826297

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Project description:RationaleGas chromatography/electron ionization mass spectrometry (GC/EI-MS) is a well-established tool for the identification of unknown compounds such as new metabolites of xenobiotics. But it reaches the limits of confident structural assignment if it comes to stereoisomers. This work helps to overcome this difficulty by getting a deeper comprehension of composition of so far unspecific and also characteristic fragment ions in general and comparison among stereoisomers.MethodsUnit mass resolution mass spectra of various isotopologues of four 17α-methyl steroid diastereomers obtained by selectively introducing [2H9]-trimethylsilyl (TMS) groups or chemical syntheses were systematically compared. The impact of stereochemistry on variations of relative abundances has been assessed by statistical comparison from repeated measurements. Additionally, characterization of m/z 318 with high-resolution MS using gas chromatography/quadrupole time-of-flight MS (GC/QTOF-MS) was performed.ResultsThe formation of fragment ions from TMS-derivatives after cleavage of methyl or TMS groups ([M-CH3]+, [M-TMSOH]•+, [M-CH3-TMSOH]+, [M-2x90]•+, [M-2x90-CH3]+) rarely arises from only one position in the molecule and composition of fragment ion signals is highly influenced by the stereochemistry of the A-ring at C3 and C5 of the steroid. Similarly, the formation of the characteristic fragment ion m/z 143 most likely consists of two different ways of formation. A possible structure for fragment ion m/z 318 was postulated.ConclusionsStereoisomers showed differing fragmentation behaviors based on their configuration. These observations further illustrate that variations among stereoisomers in EI-MS fragmentation is no random underlying process but instead a pattern which needs to be understood in its complexity. This easily accessible technical approach can be applied on different molecule structures to further investigate the field of isomeric assignment in GC/EI-MS.

Project description:H-Abstraction reactions occurring during electron impact ionization processes in electron ionization mass spectrometry (EI-MS) are a long-standing and crucial topic in MS research. Yet, some critical relevant mechanisms are controversial and ambiguous, and information about the EI-induced H-abstraction reactions of halogenated organic compounds (HOCs) is completely in the dark. This study provides a systematic investigation of H-abstraction reactions of HOCs taking place in the EI source using 13C6-hexachlorobenzene (13C6-HCB) and 13C6-hexabromobenzene (13C6-HBB) as exemplary compounds by gas chromatography (GC)-high-resolution mass spectrometry (GC-HRMS). The H-abstraction efficiencies were evaluated with the MS signal intensity ratios of ions with H-abstraction relative to the corresponding original ions (without H-abstraction). Ion source temperatures, EI energies, and numbers of heavy isotope atoms (37Cl or 81Br) of isotopologues were investigated in terms of their effects on the H-abstraction efficiencies. The H-abstraction efficiencies of individual isotopologues generally decreased from the first to the last isotopologues of respective ions, and those of individual ions were different from each other, with the highest values of 0.017 and 0.444 for 13C6-HCB and 13C6-HBB, respectively. The overall H-abstraction efficiencies involving all measured ions of 13C6-HCB and 13C6-HBB were 0.004 and 0.128, respectively. With increasing ion source temperatures, the H-abstraction efficiencies first increased to a summit and then began to linearly decrease. EI energies and emission currents could impact the H-abstraction efficiencies but showed no certain tendency. The H-abstraction reactions were inferred to belong to ion-molecule reactions, and the siloxanes bleeding from the GC column might be a hydrogen source. Some strategies were proposed for eliminating or alleviating the interference triggered by the H-abstraction reactions in EI-MS in identification of halogenated organic pollutants (HOPs). Our findings provide a better understanding of the EI-induced H-abstraction reactions of HOCs and may benefit the identification of HOPs in environmental analysis, especially for novel HOPs.

Dataset Information

A simplified method for therapeutic drug monitoring of mitotane by gas chromatography-electron ionization-mass spectrometry.

Publications

A simplified method for therapeutic drug monitoring of mitotane by gas chromatography-electron ionization-mass spectrometry.

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