Effect of the novel antipsychotic drug perospirone on P-glycoprotein function and expression in Caco-2 cells.

OBJECTIVE: Perospirone (PER) is a novel atypical antipsychotic drug for the treatment of schizophrenia and other psychotic disorders. The multidrug resistance transporter, P-glycoprotein (Pgp), is involved in the efflux transport of several antipsychotics across the blood-brain barrier (BBB). The aim of the present study was to evaluate the modulating effect of PER on both Pgp activity and expression in Caco-2 cell monolayers. METHODS: The effects of PER were analyzed by means of rhodamine 123 (Rhd 123) assays, and those of Pgp expression were analyzed by flow cytometry and reverse transcriptase-PCR. RESULTS: Perospirone at concentrations of 0.01-30 microM, which were found to be non-cytotoxic towards the Caco-2 cells, was observed to inhibit Pgp-mediated efflux transport of Rhd 123 in the cells as well as to down-regulate the cellular Pgp protein and MDR1 mRNA levels in a concentration-dependent manner. In the rhodamine accumulation assays, 30 microM PER produced a 429% increase of the cellular Rhd 123 concentration, which exceeded the inhibitory effect of the well-known Pgp inhibitor verapamil. CONCLUSION: Our findings provide experimental evidence that PER is an inhibitor of Pgp which interferes directly and indirectly with the function of Pgp.