P-glycoprotein and cytochrome P450 3A4 involvement in risperidone transport using an in vitro Caco-2/TC7 model and an in vivo model

Prog Neuropsychopharmacol Biol Psychiatry. 2007 May 9;31(4):878-86. doi: 10.1016/j.pnpbp.2007.01.028. Epub 2007 Feb 8.


The possible involvement of P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 in risperidone transport was investigated using in vitro and in vivo models. Firstly, uptake studies were performed on a Caco-2/TC7 cell monolayer; the effects of 1 microg ml(-1) risperidone on apparent permeability were determined for secretory and absorptive directions, in the presence or absence of various P-gp and CYP3A4 inhibitors (verapamil, ketoconazole, erythromycin), and of an associated multidrug-resistant protein inhibitor (indomethacin). Secondly, on a conscious rat model, risperidone pharmacokinetic parameters, notably absorption parameters, were determined using compartmental and deconvolution methods. Three groups of seven rats received respectively an IV risperidone dose, an oral risperidone dose (PO group) and the same oral risperidone dose after verapamil administration (POV group). No formation of 9-hydroxyrisperidone was observed on Caco-2 cells after risperidone administration; there was no evidence that intestinal CYP3A4 is involved in risperidone metabolising. Risperidone secretory permeation was higher than absorptive permeation. Verapamil increased risperidone absorption permeation and decreased its secretory permeation. Indomethacin did not modify these permeation values. In rats, verapamil led to an increase in both risperidone and 9-hydroxyrisperidone plasmatic concentrations. The fraction absorbed in the verapamil group was 3.18 times higher than in the oral group (65.9% and 20.7% for POV group and PO group). The absorption rate constant was lower in the verapamil group. Our results indicate that P-gp decreases the intestinal absorption of risperidone and that intestinal CYP3A4 is not involved in risperidone metabolism.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Adenocarcinoma / pathology
  • Animals
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / physiology*
  • Biological Transport / drug effects
  • Cell Line, Tumor
  • Cytochrome P450 Family 4
  • Dopamine Antagonists / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Male
  • Mixed Function Oxygenases / physiology*
  • Permeability / drug effects
  • Rats
  • Rats, Wistar
  • Risperidone / pharmacokinetics*
  • Time Factors


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Dopamine Antagonists
  • Enzyme Inhibitors
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P450 Family 4
  • cytochrome P-450 CYP4A4 (rabbit)
  • Risperidone