title: Pharmacodynamic consequences of P-glycoprotein-dependent pharmacokinetics of risperidone and haloperidol in mice.
abstract: Efflux transporters, like P-glycoprotein (P-gp), may limit the access of drugs to the brain via the blood-brain barrier. The antipsychotic drug risperidone and its active metabolite 9-hydroxyrisperidone (paliperidone) are substrates of P-gp. Motor behavior of P-gp deficient mice (mdr1a/1b (-/-, -/-)) and wild type animals on a rotarod after acute doses of risperidone or haloperidol, a nonsubstrate of P-gp, were analysed aiming to show that P-gp substrate properties of an antipsychotic drug have functional consequences. Behavioral tests revealed dose-dependent effects of 0.3-3 mg/kg risperidone in wild type animals 0.5-12 h after i.p. injection of the drug. In knockout mice the 0.3 mg/kg dose of risperidone was as effective as the 3 mg/kg dose in wild type mice. A dose of 0.3 mg/kg haloperidol, however, exhibited similar pharmacodynamic effects in both genotypes. Brain concentrations of risperidone plus 9-hydroxyrisperidone were 10-fold higher in knockout than in wild type animals whereas brain concentrations of haloperidol did not differ between the two genotypes. P-gp-dependent brain distribution kinetics and behavioral effects of risperidone give evidence that the expression of P-gp has an impact on psychotropic drug actions when treating patients with drugs that are substrates of P-gp.
authors.affiliation: Department of Psychiatry, University of Mainz, Untere Zahlbacher Strasse 8, Mainz, Germany.
authors.forename: Katrin M
authors.initials: KM
authors.lastname: Kirschbaum
authors.forename: Stefanie
authors.initials: S
authors.lastname: Henken
authors.forename: Christoph
authors.initials: C
authors.lastname: Hiemke
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schmitt
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000097:blood / Q000493:pharmacokinetics*; D007555:Isoxazoles / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000378:metabolism; D018967:Risperidone / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D014150:Antipsychotic Agents; D006220:Haloperidol; D007555:Isoxazoles; D000068882:Paliperidone Palmitate; D011743:Pyrimidines; D018967:Risperidone; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3