Pharmacodynamics and pharmacokinetics of risperidone and paliperidone with respect to P-glycoprotein expression

Efflux transporters at the blood-brain barrier, like P-glycoprotein (P-gp), limit the access of several substances to the brain. Previous studies demonstrated an active transport of the antipsychotic drug risperidone and its active metabolite 9-hydroxyrisperidone (paliperidone) out of the brain due to P-gp. Whether concentration differences in the central nervous system as a result of variations in P-gp expression are followed by functional consequences has not been investigated until now. In this study P-gp knockout mice were compared to wild type FVB mice under the treatment of 0.3mg/kg risperidone on a rotarod. Motor performance affected by D2-receptor antagonism of the drug was decreased and knockout rodents differed significantly (p<0.05) from equally treated wild type mice 0.5 to 12h after i.p. injection. Their abilities within the task were comparable to 10-fold higher (3mg/kg) treated P-gp expressing animals. Kinetic studies revealed that brain concentrations of risperidone and 9-hydroxyrisperidone were 10-fold higher in P-gp deficient mice than in wild type animals. The strong correlation between differences in brain levels and behavioral effects give evidence that clinical response or side effects in patients will be affected by variations in P-gp expression.