The effects of Citrus hystrix fruit on P-glycoprotein efflux transporter

Abstract

Oral route is one of the most commonly routes of drug administration. However, there are various factors influencing the absorption of orally administered drugs into systemic circulation. P-glycoprotein, an efflux transporter expressed at the intestinal membrane, is crucial for intestinal drug absorption. Drugs taken orally may have interaction with fruits or vegetables commonly consumed in normal diet. The objective of this study was to investigate the possibility of P-gp mediated drug interactions of C. hystrix. The effects of extracts and/or active compounds on P-gp function and protein expression were evaluated in vitro using Caco-2, LLC-PK1 and overexpressed human P-gp LLC-GA5-COL300. The results show that the flavedo extract significantly inhibited P-gp function. The furanocoumarins were isolated as the P-gp inhibitors with the order of inhibitory potency as follows: epoxybergamottin > dihydroxybergamottin > oxypeucedanin > bergamottin > oxypeucedanin hydrate. The mechanistic study of dihydroxybergamottin and oxypeucedanin revealed that both compounds reversibly inhibited P-gp function. Dihydroxybergamottin was likely to be P-gp inhibitor but not P-gp substrate. The IC50 values were 39.8 ± 0.8 μM and 41.5 ± 2.1 μM from the uptake and transport studies, respectively. Interestingly, oxypeucedanin was possibly both substrate and reversible inhibitor of P-gp. The IC50 values of oxypeucedanin from uptake and transport studies were 60.3 ± 1.0 μM and 50.7 ± 5.1 μM, respectively. Both dihydroxybergamottin and oxypeucedanin could down-regulate the protein expression of P-gp in a concentration dependent manner. In summary, C. hystrix fruit and its constituent furanocoumarins could inhibit P-gp function and protein expression, implying that there is a potential for P-gp mediated drug interactions with P-gp substrate drugs. On the other hand, the P-gp inhibition effect could be employed as the potential bioenhancer to improve the bioavailability of P-gp substrate drugs. However, the in vivo study should be considered to confirm their effects.

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