Abstract
Introduction:
Aripiprazole, an atypical antipsychotic drug with mixed antagonism and agonism on
dopamine D2 and serotonin receptors, is a substrate of the efflux transporter P-glycoprotein
(P-gp). Here we tested the pharmacodynamic consequences of these properties in a P-gp
deficient mouse model by studying the effects of aripiprazole and of ziprasidone on
motor coordination.
Methods:
The motor behaviour of wild-type (WT) and P-gp deficient [abcb1ab(−/−)] mice was investigated
on a RotaRod. Mice received acute injections of either aripirazole or ziprasidone.
For comparison, the dopamine receptor antagonist haloperidol and serotonin receptor
ligands buspirone and ketanserin were also applied.
Results:
Pharmacokinetic analyses revealed P-gp activity for aripiprazole and ziprasidone.
This was indicated by 3.1- and 1.9-fold higher ratios of brain to plasma concentrations
of drugs in knock-out to WT animals. Acute doses of ariprazole or ziprasidone impaired
motor behaviour on the RotaRod. Effects were similar after injection of haloperidol,
whereas the serotonin receptor ligands buspirone and ketanserin enhanced RotaRod performance.
Genotype dependent differences of motor performance were found for aripiprazole but
not for ziprasidone.
Discussion:
Evidence was given that P-gp substrate properties have pharmacodynamic consequences
for aripiprazole but not for ziprasidone and thus affect dopamine receptor related
motor behaviour.
Key words
antipsychotics - P-glycoprotein - knock-out - pharmacokinetics - pharmacodynamics
