Paliperidone (PAL) is a relatively novel atypical antipsychotic drug for schizophrenia that induces markedly varying responses. Breast cancer resistance protein (BCRP) is a recently discovered member of the ATP-binding cassette superfamily that has been used to control drug absorption, distribution and elimination, and especially to impede drug entry into the brain. To the best of our knowledge, the present study is the first to investigate the possibility of using PAL as a BCRP substrate. The intracellular accumulation and bidirectional transport were investigated using transfected 293 cell/BCRP and porcine renal endothelial cell (LLC-PK1)/BCRP cell monolayers and BCRP overexpression was confirmed by reverse transcription-quantitative polymerase chain reaction and western blot analysis. The in vitro affinity to BCRP was assessed in human BCRP (Arg482) membranes. The intracellular accumulation and bidirectional transport investigations demonstrated that BCRP can efflux PAL from cells and significantly decrease its cellular concentration over a concentration range of 0.1-50 µM. The in vitro affinity experiments indicated that PAL has a moderate affinity to BCRP at 0.1-100 µM. These results together suggest that PAL is a substrate for BCRP and that it can affect the blood-brain barrier penetration of PAL at therapeutic dosages.
Keywords: LLC-PK1/BCRP; affinity; breast cancer resistance protein; paliperidone; substrate.