First-generation antihistamines have an adverse CNS effect such as sedation, whereas second-generation antihistamine drugs are generally non-sedating. The difference in the CNS sedation profile is mainly due to the CNS penetration of the drugs. We hypothesized that the non-sedating profile is caused by low CNS penetration due to regulation by the P-glycoprotein (P-gp) efflux transporter at the blood brain barrier (BBB). A three-way crossover study with more than a 6-day washout period was performed in 8 healthy volunteers. In order to evaluate the drug interaction on P-gp, we used ebastin (Eb) from the second-generation antihistamines and verapamil (Vr) as an inhibitor of P-gp. The three study medication groups were as follows: a single oral dose of Eb 10 mg (E10); a single oral dose of Eb 20 mg (E20); and a single oral dose of Eb 10 mg together with a single oral dose of Vr 80 mg at 3 hours after Eb dosing (EV). The sedative side effect of Eb was measured by both saccadic peak velocity (SPV) analysis, as an objective evaluation, and the visual analogue self-rating scale (VAS), as a subjective evaluation. No sedative effect was observed in any group. These results suggest that Eb has no clinically significant sedative effect even when the Eb dose is increased or with co-administration of P-gp inhibitor.

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