Pharmacokinetic-pharmacodynamic modeling of the D₂ and 5-HT (2A) receptor occupancy of risperidone and paliperidone in rats

Pharm Res. 2012 Jul;29(7):1932-48. doi: 10.1007/s11095-012-0722-8. Epub 2012 Mar 22.


Purpose: A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D₂ and serotonin 5-HT(2A) receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats.

Methods: A population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D₂ and 5-HT(2A) RO data. A previously published physiology- and mechanism-based (PBPKPD) model describing brain concentrations and D₂ receptor binding in the striatum was expanded to include metabolite kinetics, active efflux from brain, and binding to 5-HT(2A) receptors in the frontal cortex.

Results: A two-compartment model best fit to the plasma PK profile of risperidone and paliperidone. The expanded PBPKPD model described brain concentrations and D₂ and 5-HT(2A) RO well. Inclusion of binding to 5-HT(2A) receptors was necessary to describe observed brain-to-plasma ratios accurately. Simulations showed that receptor affinity strongly influences brain-to-plasma ratio pattern.

Conclusion: Binding to both D₂ and 5-HT(2A) receptors influences brain distribution of risperidone and paliperidone. This may stem from their high affinity for D₂ and 5-HT(2A) receptors. Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / blood
  • Antipsychotic Agents / pharmacokinetics*
  • Antipsychotic Agents / pharmacology*
  • Brain / drug effects
  • Brain / metabolism
  • Isoxazoles / blood
  • Isoxazoles / pharmacokinetics*
  • Isoxazoles / pharmacology*
  • Male
  • Models, Biological
  • Paliperidone Palmitate
  • Pyrimidines / blood
  • Pyrimidines / pharmacokinetics*
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Receptors, Dopamine D2 / metabolism*
  • Risperidone / blood
  • Risperidone / pharmacokinetics*
  • Risperidone / pharmacology*


  • Antipsychotic Agents
  • Isoxazoles
  • Pyrimidines
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2
  • Risperidone
  • Paliperidone Palmitate