Abstract
<p class="Abstract">P-glycoprotein (P-gp) is a membrane transporter responsible for the active efflux from the cell. Inhibition of the activity may lead to clinically significant drug-drug interactions. This study was performed to investigate the effects of atorvastatin and ezetimibe on the function and expression of P-gp. The <em>in vitro</em> rhodamine-123 (Rho123) efflux assay and Western blot in Caco-2 cells, and the <em>in situ</em> rat single-pass intestinal permeability model followed by high performance liquid chromatography were developed. Rho123 intracellular accumulation in 100 µM of atorvastatin- and ezetimibe-treated cells was significantly higher than that in control cells (p&lt;0.05). P-gp expression was decreased by 100 µM atorvastatin and ezetimibe. Intestinal effective permeability of digoxin in the presence of atorvastatin (3 and 100 µM), ezetimibe (10 and 100 µM) was significantly increased (p&lt;0.05). Both drugs inhibited P-gp activity in vitro and<em> in situ</em>. Atorvastatin and ezetimibe down-regulated the expression of P-gp <em>in vitro</em>. </p><p class="Abstract"><strong>Video Clip of Methodology</strong>:</p><p class="Abstract"><a href="https://youtube.com/v/BQuz1ER3_NQ">Single-pass intestinal permeability</a>: 17 min 26 sec</p><p> </p>
Highlights
In recent years, the potential for significant clinical drug –drug interactions (DDIs) has emerged owing to the growing use of drugs and herbal medicines
The MTT cytotoxicity assay on Caco-2 cells treated with 0.1, 3, and 100 μM atorvastatin, 0.2, 10, and 100 μM ezetimibe, 300 μM verapamil and 20 μM digoxin solutions showed no cytotoxicity (Figure 2)
Statistical analyses showed that there was no significant difference in cell viability among the different treatment groups, and the concentrations used were considered for the following in vitro and in situ tests
Summary
The potential for significant clinical drug –drug interactions (DDIs) has emerged owing to the growing use of drugs and herbal medicines. The active efflux of drugs from enterocytes back into the intestinal lumen is one of the major barriers to oral drug delivery. P-glycoprotein (P-gp), an ATP binding cassette protein, is a membrane transporter responsible for the active efflux and the secretion of passively diffused drugs and xenobiotics from the cell. It is expressed on several barrier epithelia, including the small intestine, blood– brain barrier, liver, kidneys, and bile canaliculi. This multidrug transporter has broad substrate specificity, with a tendency towards lipophilic, cationic compounds. P-gp plays critical role in the absorption and excretion of drugs, and the distribution of drugs to various physiological spaces and target tissues
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