Abstract
P-glycoprotein (P-gp) is known to be involved in multidrug resistance (MDR) and modulation of pharmacokinetic (PK) profiles of substrate drugs. Here, we studied the effects of synthesized ferulic acid (FA) derivatives on P-gp function in vitro and examined PK alteration of paclitaxel (PTX), a well-known P-gp substrate drug by the derivative. Compound 5c, the FA derivative chosen as a significant P-gp inhibitor among eight FA candidates by in vitro results, increased PTX AUCinf as much as twofold versus the control by reducing PTX elimination in rats. These results suggest that FA derivative can increase PTX bioavailability by inhibiting P-gp existing in eliminating organs.
Highlights
P-glycoprotein (P-gp) is a membrane efflux transporter that is a member of the ATP-binding cassette (ABC) superfamily
It has been reported that Ferulic acid (FA) and its derivatives induce cell cycle arrest, autophagy, apoptosis and cytotoxicity in several cancer cells such as leukemia, breast cancer, cervical cancer, etc. [12,13,14]
FA derivatives were synthesized as shown in Scheme 1
Summary
P-glycoprotein (P-gp) is a membrane efflux transporter that is a member of the ATP-binding cassette (ABC) superfamily This transporter is widely distributed in normal organs including the brain [1], liver [2], intestine [3] and kidney [4] to protect our body from exogenous compounds including toxins by extruding them out of the body organs. P-gp inhibitors can be used to overcome MDR. This concept is extended to improve the absorption of orally delivered medications by inhibiting P-gp located in the gastrointestinal (GI) tract [8,9,10]. A few studies have assessed recently the effect of FA on the reversal of the P-gp-mediated MDR in cancer [15,16]. We synthesized several FA derivatives in the study and evaluated their function on P-gp in vitro and in vivo systems
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