P-glycoprotein (P-gp) affects the pharmacodynamics and of the atypical antipsychotic amisulpride

P-glycoprotein (P-gp) is an essential protein catalyzing the efflux of xenobiotics via the blood-brain barrier and is thus detrimental for the effectiveness of CNS active drugs that are substrate of P-gp. Whether active membrane transport by P-gp plays a role in the pharmacokinetics and efficacy of the atypical antipsychotic amisulpride (1.5mg/kg) was investigated in vivo. The inhibition of apomorphine-induced locomotion was investigated in rats after a single dose of amisulpride (50mg/kg) with and without coadministration of the P-gp inhibitor cyclosporine A (CsA, 50mg/kg) at several time points. Analysis of open field behavior showed time dependent abolishment in locomotion by amisulpride. The antipsychotic effect was sensitive to P-gp inhibition by CsA resulting in a higher and significantly longer antipsychotic effect (p<0.05; at 24h after drug administration). These results pointed to a remarkable influence of P-gp on pharmacodynamics of antipsychotics that are substrate of P-gp.