Effect of P-Glycoprotein on Intestinal Absorption and Brain Penetration of Antiallergic Agent Bepotastine Besilate

Abstract

ABSTRACT:The antiallergic agent bepotastine besilate is a nonsedating, second-generation H1-antagonist with high oral absorption and negligible distribution into brain. To clarify the role of P-glycoprotein (P-gp) in the pharmacokinetics of bepotastine, intestinal absorption and brain penetration studies were performed. In conclusion, bepotastine is a substrate for P-gp, and P-gp clearly limited the brain distribution of bepotastine, whereas the effect of P-gp on intestinal absorption of bepotastine was minimal, presumably because of high membrane permeability at the upper region of small intestine where P-gp is less expressed. Such intestinal absorption property of bepotastine is distinctly different from the low membrane-permeable P-gp substrate fexofenadine.First-generation H1-receptor antagonists have been used for the treatment of allergic disorders. However, they are problematic because they induce sedation as they penetrate well to the brain (Nicholson 1983, Tagawa et al., 2001. Bepotastine besilate [(ϩ)-(S)-4-{4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino}butyric acid monobenzenesulfonate, betotastine besilate, TAU-284, Talion] was developed as a second-generation H1-antagonist. Bepotastine showed a high selectivity and potent antagonistic action to H1-receptor and exerted an excellent antiallergic action (Honda et al., 1997;Kato et al., 1997;Sakai et al., 1997;Yato et al., 1997). Nonclinical and clinical studies suggested that bepotastine does not exhibit sedation at the clinical therapeutic dose because of limited distribution into brain (Kadosaka et al., 1997;Ohashi et al., 1997). Bepotastine is metabolically stable in dogs and humans and is excreted into urine in an unchanged form Ͼ70% of dose after p.o. administration. Intestinal absorption of bepotastine was Ͼ85%, Ͼ70%, and Ͼ80% in rats, dogs, and humans, respectively, showing high absorption. The variation of drug concentration in plasma after p.o. administration to healthy volunteers was small, and plasma concentration was not significantly affected by food. The tissue distribution studies of [14 C]bepotastine after p.o. administration to rats showed that [ 14 C]bepotastine distributed widely in the whole body, whereas its brain distribution was lower than that of ketotifen, terfenadine, and its carboxylic metabolite (fexofenadine) (Kato et al., 1997).The MDR1 gene (multidrug resistance; ABCB1) product P-glycoprotein (P-gp) plays an important role in pharmacokinetics of drugs. P-gp is well known as an important factor to limit membrane permeability in several tissues and/or the elimination pathways into urine and bile. P-gp is highly expressed in the endothelial cells of brain capillaries and restricts the brain penetration of drugs (Tsuji et al., 1992;Schinkel et al., 1994). Although intestinal P-gp is probably a limiting factor of intestinal absorption of drugs, it is also true that substrates of P-gp exhibit good bioavailability (Varma et al., 2005). Therefore, the effect of P-gp on intestinal drug absorption is controversial compared with ...

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