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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Proteolytic stability in gastrointestinal tract and blood plasma is the major obstacle for oral peptide drug development. Inhibitor cystine knots (ICKs) are linear cystine knot peptides which have multifunctional properties and could become promising drug scaffolds. ProTx-I, ProTx-II, GTx1-15, and GsMTx-4 were spider-derived ICKs and incubated with pepsin, trypsin, chymotrypsin, and elastase in physiological conditions to find that all tested peptides were resistant to pepsin, and ProTx-II, GsMTx-4, and GTx1-15 showed resistance to all tested proteases. Also, no ProTx-II degradation was observed in rat blood plasma for 24 hours in vitro and ProTx-II concentration in circulation decreased to half in 40 min, indicating absolute stability in plasma and fast clearance from the system. So far, linear peptides are generally thought to be unsuitable in vivo, but all tested ICKs were not degraded by pepsin and stomach could be selected for the alternative site of drug absorption for fast onset of the drug action. Since spider ICKs are selective inhibitors of various ion channels which are related to the pathology of many diseases, engineered ICKs will make a novel class of peptide medicines which can treat variety of bothering symptoms.

HighlightsHuman Kv2.1 was expressed in the inner membrane of E. coli using prokaryotic codon.Bacterial spheroplasts large enough for the automated patch clamp were prepared by microfluidic chips.Kv2.1 current was recorded from the giant spheroplast by the automated patch clamp.E. coli spheroplasts were used for dose–response assay of potassium channel inhibitors.Our system will become the simple and sensitive drug assay method anyone can use.

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