期刊
ACTA PHARMACEUTICA SINICA B
卷 11, 期 5, 页码 1213-1226出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2021.01.009
关键词
FLZ; Parkinson's disease; Gut microbiota; CYP51; COMT
资金
- National Sciences Foundation of China [81773718, 81630097, 81773589]
- National Key Research and Development Program of China [SQ2018YFA090025-04]
- CAMS Innovation Fund for Medical Sciences, (China) [2016-I2M-3-011]
- Drug Innovation Major Project, (China) [2018ZX09711001-003-020, 2018ZX09711001003-005, 2018ZX09711001-008-005]
- CAMS The Fundamental Research Funds for the Central Universities, (China) [2018RC350002]
The gut microbiota plays a crucial role in mediating the absorption of FLZ, a novel squamosamide derivative with neuroprotective effects on Parkinson's disease models. Dysbiosis can reduce the therapeutic efficacy of FLZ by inhibiting its absorption in the gut.
The gut microbiota plays an important role in regulating the pharmacokinetics and pharmacodynamics of many drugs. FLZ, a novel squamosamide derivative, has been shown to have neuroprotective effects on experimental Parkinson's disease (PD) models. FLZ is under phase I clinical trial now, while the underlying mechanisms contributing to the absorption of FLZ are still not fully elucidated. Due to the main metabolite of FLZ was abundant in feces but rare in urine and bile of mice, we focused on the gut microbiota to address how FLZ was metabolized and absorbed. In vitro studies revealed that FLZ could be exclusively metabolized to its major metabolite M1 by the lanosterol 14 alpha-demethylase (CYP51) in the gut microbiota, but was almost not metabolized by any other metabolism-related organs, such as liver, kidney, and small intestine. M1 was quickly absorbed into the blood and then remethylated to FLZ by catechol O-methyltransferase (COMT). Notably, dysbacteriosis reduced the therapeutic efficacy of FLZ on the PD mouse model by inhibiting its absorption. The results show that the gut microbiota mediate the absorption of FLZ through a FLZ-M1-FLZ circulation. Our research elucidates the vital role of the gut microbiota in the absorption of FLZ and provides a theoretical basis for clinical pharmacokinetic studies and clinical application of FLZ in the treatment of PD. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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