Abstract
Emodin, a major active anthraquinone, frequently interacts with other drugs. As changes of efflux transporters on intestine are one of the essential reasons why the drugs interact with each other, a validated Ussing chamber technique was established to detect the interactions between emodin and efflux transporters, including P-glycoprotein (P-gp), multidrug-resistant associated protein 2 (MRP2), and multidrug-resistant associated protein 3 (MRP3). Digoxin, pravastatin, and teniposide were selected as the test substrates of P-gp, MRP2, and MRP3. Verapamil, MK571, and benzbromarone were their special inhibitors. The results showed that verapamil, MK571, and benzbromarone could increase digoxin, pravastatin, and teniposide absorption, and decrease their Er values, respectively. Verapamil (220 μM) could significantly increase emodin absorption at 9.25 μM. In the presence of MK571 (186 μM), the Papp values of emodin from M-S were significantly increased and the efflux ratio decreased. With the treatment of emodin (185, 370, and 740 μM), digoxin absorption was significantly decreased while teniposide increased. These results indicated that emodin might be the substrate of P-gp and MRP2. Besides, it might be a P-gp inducer and MRP3 inhibitor on enterocyte, which are reported for the first time. These results will be helpful to explain the drug–drug interaction mechanisms between emodin and other drugs and provide basic data for clinical combination therapy.
Highlights
Emodin (1,3,8trihydroxy-6-methylanthraquinone), a major active anthraquinone, is naturally present in some herbs which have been wildly used in Oriental countries, such as Rheum officinale Baill., Polygonum multijiorum Thunb., Polygonum cuspidatum Sieb
The results showed that the inhibitors, including verapamil, MK571, and benzbromarone, could significantly validation study, the concentrations of the inhibitor increase the absorption of the aforesaid substances and inhibit were set at 220 and 440 μM for the small intestine segments their secretion, and their Er values were decreased
In multidrug-resistant associated protein 2 (MRP2) and multidrug-resistant associated protein 3 (MRP3) validation studies, the inhibitors MK571 (186 μM) and benzbromarone (470 μM) were displayed significant inhibition effect on both jejunum and ileum. These results indicated that the Ussing chamber technique could be used to investigate the role of P-gp, MRP2, and MRP3 in drug intestinal transport studies
Summary
Emodin (1,3,8trihydroxy-6-methylanthraquinone), a major active anthraquinone, is naturally present in some herbs which have been wildly used in Oriental countries, such as Rheum officinale Baill., Polygonum multijiorum Thunb., Polygonum cuspidatum Sieb. Emodin has been shown a wide spectrum of biological and pharmacological effects, such as hepatoprotective antiviral, anti-diabetic, anti-bacterial, antiallergic, anti-osteoporotic, immunosuppressive, and neuroprotective activities (Dong et al, 2016; Monisha et al, 2016). Drug–drug interactions between emodin and other drugs attracted more and more researchers’ attention. Many studies have shown synergistic effects between emodin and other antineoplastic drugs (Ko et al, 2010; Wang et al, 2010; Tan et al, 2011; Guo et al, 2013). There were no reports about the research of emodin direct effects on intestinal transporters
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