Gut microbiota mediates the absorption of FLZ,a new drug for Parkinson's disease treatment

• 作者: Junmei Shang Shurong Ma Caixia Zang Xiuqi Bao Yan Wang Dan Zhang
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（5）
• 所属期刊栏目: Original articles
• 页码范围: 1213-1226
• 页数: 14页
• 语种: 英文

摘要

The gut microbiota plays an important role in regulating the pharmacokinetics and pharma-codynamics of many drugs.FLZ,a novel squamosamide derivative,has been shown to have neuropro-tective 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 effi-cacy 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 pharma-cokinetic studies and clinical application of FLZ in the treatment of PD.