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EFFECT OF P-GLYCOPROTEIN ON INTESTINAL ABSORPTION AND BRAIN PENETRATION OF ANTIALLERGIC AGENT BEPOTASTINE BESILATE

Exploratory DMPK, Exploratory Toxicology and DMPK Research Laboratories, Tanabe Seiyaku Co., Ltd., Saitama, Japan (R.O., Y.K., M.S., H.F.); GenoMembrane, Inc., Yokohama, Japan (H.Y.); and Department of Molecular Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan (I.T.)

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. [¹⁴C]Bepotastine transport in P-gp-overexpressed LLC-PK1 cells indicated that bepotastine was a substrate of P-gp. The affinity of bepotastine to P-gp estimated by ATPase activity assay was low, with a K_m value of 1.25 mM. After i.v. administration, the brain/plasma free concentration ratio in mdr1-knockout mice was 3 times higher than that in wild-type mice. The in situ intestinal absorption studies of [¹⁴C]bepotastine in rats showed a clear regional difference, showing highest permeability at the upper part of small intestine with a decreasing permeability in the descending part of small intestine. The apparent absorption rate constant (ka) of [¹⁴C]bepotastine in the small intestine was greatly increased by cyclosporin A and verapamil, especially in the distal portion, and the site-specific absorption of [¹⁴C]bepotastine disappeared. The concentration dependence of ka of [¹⁴C]bepotastine was observed with a higher ka at higher concentration (20 mM) compared with that at lower concentration (1 µM). 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.

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