Multi-Drug-Resistance proteins affect antipsychotic treatment: in vivo effects of aripiprazole

Multi Drug Resistance (MDR) carriers in the Blood-Brain-Barrier (BBB) protect the brain from pharmacological tissue damage. Of all of the MDR xenobiotic efflux pumps highly expressed in the BBB p-glycoprotein (p-gp, MDR1) handles the largest fraction of commonly prescribed drugs. We investigated the role of p-gp on metabolic (pharmacokinetic) and behavioral (pharmacodynamic) effects of aripiprazole (ari) in a p-gp k.o. mouse model (mdr1a/b -/-). Wild type and transgenic mice were acutely treated (i.p.) with either aripiprazole or its active metabolite dehydroaripiprazole (d-ari), or saline. Blood serum and brain tissue levels were measured 1,3,6,9, and 24h after injection. Behavioral changes were analysed on a rotarod and in the radial water maze learning task 0.5h after treatment. Kinetic investigation revealed significant differences (p<0.05) between both genotypes for ari (10mg/kg) and for d-ari in both serum and brain tissue. In wild type mice both substances affected locomotor behavior significantly (ari 1 and 5mg/kg; d-ari 1mg/kg). In transgenic mice this effect was significantly increased. For learning behavior (ari/d-ari 1mg/kg) the difference between both genotypes was not as prominent as on the rotarod. These results give strong evidence that aripiprazole as well as its active metabolite dehydroaripiprazole are substrates of p-gp and that this has consequences for clinical outcome.