title: Pharmacodynamic effects of aripiprazole and ziprasidone with respect to p-glycoprotein substrate properties.
abstract: BACKGROUND
  Aripiprazole, an atypical antipsychotic drug with mixed antagonism and agonism on dopamine D2 and serotonin receptors, is a substrate of the efflux transporter P-glycoprotein (P-gp). Here we tested the pharmacodynamic consequences of these properties in a P-gp deficient mouse model by studying the effects of aripiprazole and of ziprasidone on motor coordination.
  
  
  METHODS
  The motor behaviour of wild-type (WT) and P-gp deficient [abcb1ab(-/-)] mice was investigated on a RotaRod. Mice received acute injections of either aripirazole or ziprasidone. For comparison, the dopamine receptor antagonist haloperidol and serotonin receptor ligands buspirone and ketanserin were also applied.
  
  
  RESULTS
  Pharmacokinetic analyses revealed P-gp activity for aripiprazole and ziprasidone. This was indicated by 3.1- and 1.9-fold higher ratios of brain to plasma concentrations of drugs in knock-out to WT animals. Acute doses of ariprazole or ziprasidone impaired motor behaviour on the RotaRod. Effects were similar after injection of haloperidol, whereas the serotonin receptor ligands buspirone and ketanserin enhanced RotaRod performance. Genotype dependent differences of motor performance were found for aripiprazole but not for ziprasidone.
  
  
  CONCLUSIONS
  Evidence was given that P-gp substrate properties have pharmacodynamic consequences for aripiprazole but not for ziprasidone and thus affect dopamine receptor related motor behaviour.
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Holthoewer
authors.forename: K M
authors.initials: KM
authors.lastname: Kirschbaum
authors.forename: J
authors.initials: J
authors.lastname: Frisch
authors.forename: C
authors.initials: C
authors.lastname: Hiemke
authors.forename: U
authors.initials: U
authors.lastname: Schmitt
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000068180:Aripiprazole; D002065:Buspirone / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D045442:Rotarod Performance Test; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; C092292:ziprasidone; D000068180:Aripiprazole; D007650:Ketanserin; D006220:Haloperidol; D002065:Buspirone