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.


CONCLUSIONS
Our findings provide experimental evidence that PER is an inhibitor of Pgp which interferes directly and indirectly with the function of Pgp.
Zhou
Yan-Gang
YG
The Clinical Pharmacy & Pharmacology Institute, XiangYa Second Hospital, Central South University, Changsha 410011, China.
Li
Kun-Yan
KY
Li
Huan-De
HD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001483:Base Sequence; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D054833:Isoindoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020112:Rhodamine 123 / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D017931:DNA Primers; D054833:Isoindoles; D012333:RNA, Messenger; D013844:Thiazoles; D020112:Rhodamine 123; C065533:perospirone