1. ¹Laboratory of Drug Disposition and Pharmacogenetics, Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC, USA
2. ²Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA

Correspondence: Dr CL DeVane, Laboratory of Drug Disposition and Pharmacogenetics, Medical University of South Carolina, 173 Ashley Avenue, Room 405B, Charleston, SC 29425, USA. Tel: +1 843 792 5448, Fax: +1 843 792 6318, E-mail: devaneL@musc.edu

Received 9 February 2006; Revised 23 June 2006; Accepted 1 July 2006; Published online 23 August 2006.

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 IC₅₀ values of RSP for inhibiting P-gp-mediated transport of Rh123 and DOX were 63.26 and 15.78 M, respectively, whereas the IC₅₀ values of PALI were >100 M, 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 M, significantly enhanced the intracellular accumulation of Rh123 in Caco-2 cells by inhibiting P-gp activity with an IC₅₀ value of 5.87 M. Following exposure to 10 M 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.