Pharmacokinetic Studies of Betotastine Besilate (TAU-284). (I): Absorption, Distribution, Metabolism and Excretion after a Single Oral Administration.

Ohashi, Rikiya; Tsukimoto, Mikiko; Nakamura, Susumu; Ohtsuka, Minezo; Hayashi, Kazushi; Nishiyama, Shin-itirou; Hanawa, Shinya; Mitsugi, Koichi; Esumi, Yoshio

doi:10.2133/dmpk.12.417

Cited by 4 publications

(3 citation statements)

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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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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Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…Excretion of dosed radioactivity was 39.7 and 61.6% in urine and feces, respectively, within 120 h of oral administration in male rats. Biliary excretion accounted for 40.6% of the dose administered, and most appeared to be subjected to enterohepatic circulation (11).…”

Section: Toxicitymentioning

confidence: 99%

Betotastine besilate

Graul¹,

Castañer²

1998

Drugs of the Future

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The antiallergic activity of betotastine besilate was evaluated in comparison to that of other compounds in various rat models of allergy. Betotastine besilate inhibited histamine release from rat peritoneal mast cells and inhibited LTB 4 and 5-HETE production in peritoneal cells at high concentrations (1 mM). Following oral administration at doses ranging from 0.1-30 mg/kg p.o., betotastine inhibited the homologous passive cutaneous anaphylaxis (PCA) reaction in a dose-dependent fashion (ID 30 = 0.38 mg/kg p.o.), an effect which lasted for more than 8 h. This effect was significant at a dose of 1 mg/kg, and was superior to that of ketotifen, terfenadine, cetirizine and epinastine. No tolerance developed following administration to rats for 8 days (2). The compound also dose-dependently inhibited histamine-induced allergic skin reactions in rats (ID 30 = 0.10 mg/kg), with the effect lasting for more than 4 h postdosing. This effect was significant at doses of 0.1 and 1.0 mg/kg, and was again superior to that of the above reference compounds. Oral betotastine (30 mg/kg) suppressed to decrease in histamine content in pleural cells in a rat model of concanavalin A-induced pleurisy. Taken together, these results indicate that betotastine besilate is a potent and long-acting antiallergic agent whose activity is due to histamine antagonism (2). The antiallergic activity of betotastine was also evaluated in several guinea pig models of bronchoconstriction (2-4). Like the reference compounds ketotifen, terfenadine and cetirizine, betotastine besilate dose-dependently prevented severe asthmatic reactions induced in guinea pigs by histamine inhalation or antigen exposure (ED 50 = 0.01 and 0.3 mg/kg p.o., respectively). The compound also inhibited antigen-induced airway hyperresponsiveness in acutely sensitized guinea pigs at doses of 1 mg/kg p.o. or higher (3).

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“…10 -7 M when administered orally at 10 mg in humans [10] . Given that the concentration of bepotastine in the skin is comparable with the plasma level [11] , its in vitro suppressive concentration is considered to be biologically meaningful. To examine the effect on CD54 expression, NHEK were incubated with 200 unit/ml IFN-␥ with or without bepotastine for 48 h. Bepotastine at 3 !…”

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Downmodulatory Effects of the Antihistaminic Drug Bepotastine on Cytokine/Chemokine Production and CD54 Expression in Human Keratinocytes

Miwa¹,

Kabashima²,

Nakamura³

et al. 2008

Skin Pharmacol Physiol

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Bepotastine besilate is an antihistaminic drug of the second generation with superior clinical responses. In this study, we investigated whether bepotastine modulates the production of cytokines/chemokines and the expression of CD54 in human epidermal keratinocytes. The production of IL-1α, CXCL10, and CCL17 and the expression of CD54 were significantly suppressed by the addition of bepotastine. Bepotastine exerts its antiallergic action on keratinocytes by suppressing the production of certain proinflammatory cytokines, both Th1 and Th2 chemokines, and possibly by inhibiting the expression of CD54.

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Pharmacokinetic Studies of Betotastine Besilate (TAU-284). (I): Absorption, Distribution, Metabolism and Excretion after a Single Oral Administration.

Cited by 4 publications

References 1 publication

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

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

Betotastine besilate

Downmodulatory Effects of the Antihistaminic Drug Bepotastine on Cytokine/Chemokine Production and CD54 Expression in Human Keratinocytes

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