Quantitative determination of D4-cystine in mice using LC-MS/MS and its application to the assessment of pharmacokinetics and bioavailability

Cystine is the primary source material for the synthesis of glutathione. However, the pharmacokinetics and tissue distribution of cystine are largely unknown. A surrogate analyte D4-cystine was employed to generate calibration curves for the determination of levels of D4-cystine and endogenous cysti...

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Bibliographic Details
Published in:Journal of pharmaceutical analysis 2021-10, Vol.11 (5), p.580-587
Main Authors: Li, Shuning, Lu, Zhenyao, Jiao, Li, Zhang, Ran, Hong, Yu, Aa, Jiye, Wang, Guangji
Format: Article
Language:English
Subjects:
Absolute bioavailability
Bioavailability
Calibration
Chromatography
Cystine
Distribution
Glutathione
Hepatitis
Kidneys
Laboratory animals
LC-MS/MS
Liquid chromatography
Liver
Mass spectrometry
Mass spectroscopy
Original
Pharmacokinetics
Plasma
Plasma levels
Reagents
Scientific imaging
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Summary:Cystine is the primary source material for the synthesis of glutathione. However, the pharmacokinetics and tissue distribution of cystine are largely unknown. A surrogate analyte D4-cystine was employed to generate calibration curves for the determination of levels of D4-cystine and endogenous cystine in mice by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Validation assessments proved the sensitivity, specificity and reproducibility of the method with a lower limit of quantification (LLOQ) of 5 ng/mL over 5–5000 ng/mL in plasma. The pharmacokinetics of D4-cystine were evaluated after administering injections and oral solutions, both of which minimally impacted endogenous cystine levels. The absolute bioavailability of cystine was 18.6%, 15.1% and 25.6% at doses of 25, 50 and 100 mg/kg, respectively. Intravenously injected D4-cystine resulted in dramatically high plasma levels with reduced levels in the brain and liver. Intragastrically administered D4-cystine resulted in high levels in the plasma and stomach with relatively low levels in the lung, kidney, heart and brain. [Display omitted] •An LC-MS/MS method was developed to determine exogenous and endogenous cystine with an isotope-labelled surrogate analyte.•The pharmacokinetics of D4-cystine were assessed after i.v./i.g. administration and the absolute bioavailability was evaluated.•For the first time, the distribution of D4-cystine was profiled in diverse tissues/organs after i.v./i.g. administration.
ISSN:2095-1779
2214-0883
DOI:10.1016/j.jpha.2020.08.010