title: Pharmacokinetic-pharmacodynamic modeling of the D₂ and 5-HT (2A) receptor occupancy of risperidone and paliperidone in rats.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD, Groningen, The Netherlands.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kozielska
authors.forename: Martin
authors.initials: M
authors.lastname: Johnson
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Pilla Reddy
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.forename: Cheryl
authors.initials: C
authors.lastname: Li
authors.forename: Sarah
authors.initials: S
authors.lastname: Grimwood
authors.forename: Rik
authors.initials: R
authors.lastname: de Greef
authors.forename: Geny M M
authors.initials: GM
authors.lastname: Groothuis
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Proost
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D007555:Isoxazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D018967:Risperidone / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D018967:Risperidone; D000068882:Paliperidone Palmitate