Abstract
P-glycoprotein (P-gp) plays a major role in oral absorption of drugs. Induction or inhibition of P-gp by drugs contributes to variability of its transport activity and often results in clinically relevant drug-drug interactions. The purpose of this study was to investigate the effect of cetirizine, a second generation H1 antihistamine, on P-gp function and expression in vitro and in situ. The in-vitro rhodamin-123 (Rho123) efflux assay in Caco-2 cells was used to study the effect of cetirizine on P-gp function. Western blot analysis was used for surveying the effect of cetirizine on expression of P-gp in Caco-2 cells. Rat in situ single-pass intestinal permeability technique was used to calculate the intestinal permeability of a known P-gp substrate (digoxin) in the presence of cetirizine. The amounts of digoxin and cetirizine in intestinal perfusion samples were analyzed using a HPLC method. The results showed significant increase in Rho123 uptake (P < 0.05) and also P-gp band intensity decrease in cetirizine-treated cells in vitro. Furthermore the intestinal permeability of digoxin was also increased significantly in the presence of cetirizine (P < 0.01). Therefore it is concluded that cetirizine is a P-gp inhibitor and this should be considered in co administration of cetrizine with other P-gp substrate drugs. Further investigations are required to confirm our results and to determine the mechanism underlying P-gp inhibition by cetirizine.
Highlights
Most drugs used in clinical practice are administered orally and must be adequately and consistently absorbed to achieve successful therapy
Preliminary experiments showed that no considerable adsorption of compounds on the tubing and syringe took place and the stock and working standard solutions of cetirizine in water was stable during the experiments.[9]
Cetirizine, verapamil, and digoxin solutions showed no cytotoxicity on Caco-2 cells under the maximum dosage (100, 300, and 20 μM, respectively) (Figure 3)
Summary
Most drugs used in clinical practice are administered orally and must be adequately and consistently absorbed to achieve successful therapy. P-glycoprotein (P-gp) is the most important membrane transporter which is responsible for secreting (active efflux) passively diffused drugs and xenobiotics out of the cell.[2,3] P-gp is an ATP binding cassette protein and plays a major role in drug absorption and distribution due to its abundant expression on several barrier epithelia (including the epithelial cells of intestine, kidney, liver, brain, testis, adrenal gland, placenta, and bile canalicula) and its broad substrate specificity.[3] Some drugs, foods, and chemicals may be substrates of P-gp. Cetirizine is a piperazine derivative and is marketed as a racemic mixture containing both levocetirizine and dextrocetirizine It is a long-acting non-sedative antihistamine and an antagonist of H1-receptor. Cetirizine di-hydrochloride is used for symptomatic treatment of allergic conditions including seasonal allergic rhinitis and chronic urticarial.[7,8,9]
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