The effect of inhibition of a transporter on sedation after antihistamine administration.

It is well known that antihistamines produce sedation and that the magnitude of sedation varies between individual drugs. First generation antihistamines are lipophilic. Therefore, they can easily cross the blood-brain barrier (BBB) and block histamine H1-receptors in the central nervous system, which causes the sedation. Because second generation antihistamines are more lipophobic they cause less sedation. However, other factors, such as P-glycoprotein (Pgp) mediated efflux of the BBB may also determine the presence, absence and/or magnitude of sedation. The Pgp transporter can pump drugs out of the brain, resulting in a reduction of undesired effects in the central nervous system. Studies in experimental animals have demonstrated that the Pgp transporter is involved in the lack of sedative effects of certain antihistamines. However, so far, no human studies have been conducted in order to study the effects of the Pgp transporter on sedation caused by antihistamines. In other words, so far there is no data available to confirm whether Pgp inhibition plays a role in the impairing effects of antihistamines in humans as well. Therefore, this study will focus on the effect of the Pgp transporter on antihistamines in healthy volunteers. Taken previous findings into consideration, it is hypothesized that the behavioral effect (i.e. slower RT and impaired attention) of a non-sedative antihistamine will be apparent in combination with a Pgp-blocker, but will not be apparent when administered alone. This, because when a non-sedative antihistamine is not pumped out of the brain by the Pgp transporter, the antihistamine is able to bind at the H1R and will cause cognitive side effects, comparable with sedative antihistamines.

It is hypothesized that the behavioral effect (i.e. slower RT and impaired attention) of a non-sedative antihistamine will be apparent in combination with a Pgp-blocker, but will not be apparent when administered alone. This, because when a non-sedative antihistamine is not pumped out of the brain by the Pgp transporter, the antihistamine is able to bind at the H1R and will cause cognitive side effects, comparable with sedative antihistamines.

Two testperiods.

There are two testdays, with two fMRI scan sessions per testday.


The first (randomly assigned) testday consists of the following treatments:

Before scan 1: Placebo and 90 minutes later, before scan 2: Verapamil 120 mg.



The second testday consists of the following treatments:

Before scan 1: Cetirizine 15 mg and 90 minutes later, before scan 2: Verapamil 120 mg.



Eventually, the placebo condition of day 1 and the cetirizine condition of day 2 are compared, as well as the verapamil condition of day 1 and the verapamil condition of day 2 (with cetirizine still in the body's system) are compared.