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. [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 Km 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.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.007559.
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ABBREVIATIONS: P-gp, P-glycoprotein; BBB, blood-brain barrier; LC-MS, liquid chromatography mass spectrometry; Papp, apparent permeability coefficient; B-to-A, basal to apical; A-to-B, apical to basal; CFR, corrected flux ratio; KO, knockout; WT, wild type; CMC, carboxymethyl cellulose; P-gp KO, mdr1a/1b(–/–); ka, apparent first-order absorption rate constant; Kp,f, brain/plasma free concentration ratio.
- Received September 28, 2005.
- Accepted January 31, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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