Bioassay-guided isolation of potential intestinal absorption enhancers from Citrus reticulata Blanco
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Abstract
Overcoming intestinal P-glycoprotein (P-gp) function is one strategy to enhance the oral bioavailability of P-gp substrate drugs. This study aimed to use bioassay‑guided fractionation to isolate natural bio-enhancers from tangerine (Citrus reticulata Blanco). Isolation of bioactive compounds in cells based on P-gp inhibition activity was conducted. Rhodamine 123 uptake in Caco-2, and calcein acetoxymethyl ester uptake in LLC-PK1 versus human P-gp overexpressed LLC-GA5-Col300, were employed to identify P-gp inhibitors. The investigation revealed four active polymethoxyflavones: 5-hydroxy-6,7,8,3¢,4¢-pentamethoxyflavone; 6,7,8,4¢-tetramethoxyflavone; 5,6,7,8,4¢-pentamethoxyflavone (tangeretin); and 5,6,7,8,3¢,4¢-hexamethoxyflavone (nobiletin). Nobiletin was found to be the most significant human P-gp inhibitor in tangerine juice. This study also demonstrated the roles of 6,7,8,4¢-tetramethoxyflavone and 5-hydroxy-6,7,8,3¢,4¢-pentamethoxyflavone as P-gp inhibitors, which had not been previously explored. In summary, all isolated polymethoxyflavones demonstrated their potential roles as absorption bio-enhancers. However, their effectiveness should be substantiated by conducting more mechanistic and clinical studies.
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