title: Risperidone and paliperidone inhibit p-glycoprotein activity in vitro.
abstract: Risperidone (RSP) and its major active metabolite, 9-hydroxy-risperidone (paliperidone, PALI), are substrates of the drug transporter P-glycoprotein (P-gp). The goal of this study was to examine the in vitro effects of RSP and PALI on P-gp-mediated transport. The intracellular accumulation of rhodamine123 (Rh123) and doxorubicin (DOX) were examined in LLC-PK1/MDR1 cells to evaluate P-gp inhibition by RSP and PALI. Both compounds significantly increased the intracellular accumulation of Rh123 and DOX in a concentration-dependent manner. The IC(50) values of RSP for inhibiting P-gp-mediated transport of Rh123 and DOX were 63.26 and 15.78 microM, respectively, whereas the IC(50) values of PALI were >100 microM, indicating that PALI is a less potent P-gp inhibitor. Caco-2 and primary cultured rat brain microvessel endothelial cells (RBMECs) were utilized to investigate the possible influence of RSP on intestinal absorption and blood-brain barrier (BBB) transport of coadministered drugs that are P-gp substrates. RSP, 1-50 microM, significantly enhanced the intracellular accumulation of Rh123 in Caco-2 cells by inhibiting P-gp activity with an IC(50) value of 5.87 microM. Following exposure to 10 microM RSP, the apparent permeability coefficient of Rh123 across Caco-2 and RBMECs monolayers was increased to 2.02 and 2.63-fold in the apical to basolateral direction, but decreased to 0.37 and 0.21-fold in the basolateral to apical direction, respectively. These data suggest that RSP and PALI, to a lesser extent, have a potential to influence the pharmacokinetics and hence the pharmacodynamics of coadministered drugs via inhibition of P-gp-mediated transport. However, no human data exist that address this issue. In particular, RSP may interact with its own active metabolite PALI by promoting its brain concentration through inhibiting P-gp-mediated efflux of PALI across endothelial cells of the BBB.
authors.affiliation: Laboratory of Drug Disposition and Pharmacogenetics, Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Hao-Jie
authors.initials: HJ
authors.lastname: Zhu
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Wang
authors.forename: John S
authors.initials: JS
authors.lastname: Markowitz
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Donovan
authors.forename: Bryan B
authors.initials: BB
authors.lastname: Gibson
authors.forename: C Lindsay
authors.initials: CL
authors.lastname: DeVane
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000493:pharmacokinetics; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000494:pharmacology*; D000068882:Paliperidone Palmitate; D021381:Protein Transport / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D018967:Risperidone / Q000494:pharmacology*; D013552:Swine; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D020112:Rhodamine 123; D004317:Doxorubicin; D018967:Risperidone; D000068882:Paliperidone Palmitate