β-cyclodextrin has a unique annular hollow ultrastructure that allows encapsulation of various poorly water-soluble drugs in the resulting cavity, thereby increasing drug stability. As a bioactive molecule, the metabolism of β-cyclodextrin is mainly completed by the flora in the colon, which can interact with API. In this study, understanding the in vivo fate of β-cyclodextrin, a LC-MS/MS method was developed to facilitate simultaneous quantitative analysis of pharmaceutical excipient β-cyclodextrin and API dextromethorphan hydrobromide. The established method had been effectively used to study the pharmacokinetics, tissue distribution, excretion, and metabolism of β-cyclodextrin after oral administration in rats. Results showed that β-cyclodextrin was almost wholly removed from rat plasma within 36 h, and high concentrations of β-cyclodextrin distributed hastily to organs with increased blood flow velocities such as the spleen, liver, and kidney after administration. The excretion of intact β-cyclodextrin to urine and feces was lower than the administration dose. It can be speculated that β-cyclodextrin metabolized to maltodextrin, which was further metabolized, absorbed, and eventually discharged in the form of CO2 and H2O. Results proved that β-cyclodextrin, with relative low accumulation in the body, had good safety. The results will assist further study of the design and safety evaluation of adjuvant β-cyclodextrin and promote its clinical development.
Background
Lung cancer remains the leading cause of mortality from malignant tumors, non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases, and individualized diagnosis and treatment is an effective trend. The individual characteristics of different traditional Chinese medicine (TCM) syndromes of NSCLC patients may be revealed by highly specific molecular profiles.
Methods
In this study, 10 NSCLC patients with Qi deficiency and Yin deficiency (QDYD) syndrome and 10 patients with Qi deficiency of lung-spleen (QDLS) syndrome in TNM stage III-IV as well as 10 healthy volunteers were enrolled. Aiming at the varied syndromes of NSCLC patients with “Yin deficiency” as the main difference, a proteomics research based on data-independent acquisition (DIA) was developed. Of the dysregulated proteins in NSCLC patients, lipid metabolism was significantly enriched. Thereafter, nontargeted lipidomics research based on UPLC-Q-TOF/MS was performed in 16 patients, with 8 individuals randomly selected from each syndrome group. Furthermore, the considerably different characteristics between the syndromes and pathological mechanisms of NSCLC were screened by statistical and biological integrations of proteomics and lipidomics and the differential metabolic pathways of the two similar syndromes were further explored. Besides, lipids biomarkers were verified by a clinically used anticancer Chinese medicine, and the level of key differential proteins in the two syndromes was also validated using ELISA.
Results
The results showed that glycerophospholipid metabolism, sphingolipid metabolism, glycolipid metabolism, and primary bile acid biosynthesis were altered in NSCLC patients and that glycerophospholipid metabolism was significantly changed between the two syndromes in lipidomics analysis. Among the proteins and lipids, ALDOC and lysophosphatidylcholine (LPCs) were revealed to have a strong relationship by statistical and biological integration analysis, and could effectively distinguish QDLS and QDYD syndromes. Notably, the patients with different syndromes had the most typical metabolic patterns in glycerophospholipid metabolism and glycolysis, reflecting the differences in the syndromes dominated by “Yin deficiency”.
Conclusions
ALDOC and LPCs could be employed for the differentiation of NSCLC patients with QDLS and QDYD syndromes, and “Yin deficiency” might be associated with glycerophospholipid metabolism and glycolysis pathway. The results provided a theoretical basis for “Syndrome differentiation” in TCM diagnosis. Moreover, the developed integrated strategy could also provide a reference for individualized diagnosis and treatment of other diseases.
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