Role of Citrus Limonoid as a Possible Bioavailability Enhancer

Abstract

The oral delivery is the most practical route to deliver drugs into the body, however drug-metabolizing enzymes and drug transporters can play important roles in modulating drug absorption. This study intended to find a natural bioenhancer for improving drug bioavailability. Two limonoids, including limonin deepoxy and nomilin, isolated from pomelo pulp were studied and the inhibition effects on human CYP3A4 and P-gp were investigated. Testosterone 6β-hydroxylation was performed in recombinant human CYP3A4 to discover the effects on CYP activity. Daunorubicin transport in Caco-2 and calcein-AM uptake in LLC-PK1 and LLC-GA5-COL300 were conducted to evaluate the effects on P-gp function. The results show that both limonin deepoxy and nomilin could inhibit CYP3A4 and only nomilin exhibited mechanism-based inhibition. Nomilin was able to inhibit human P-gp in the concentration-dependent manner. Taken together, nomilin demonstrated strong activities on both CYP3A4 and P-gp, indicating that nomilin could possibly be used as a bioavailability enhancer.