Pharmacokinetic Studies of Betotastine Besilate (TAU-284). (II): Distribution and Excretion after Repeated Oral Administration, and Transfer into the Fetus and Milk of Rats.

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

doi:10.2133/dmpk.12.439

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“…Radioactivity in the milk and lactating female rats peaked (0.40 µg eq./ml) at 1 h postdosing; at 48 h after drug administration, radioactivity had dropped below the limits of detection. However, at each determination point, levels in milk were higher than those in plasma (12). to be 100 mg/kg p.o.…”

Section: Toxicitymentioning

confidence: 79%

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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Section: Toxicitymentioning

confidence: 79%