title: In vitro P-glycoprotein affinity for atypical and conventional antipsychotics.
abstract: The transmembrane transporter P-glycoprotein (P-gp) is an ATP-dependent efflux pump for a wide range of drugs. P-gp potentially limits access to brain tissue of psychoactive substrates, but little is known about its specificity for antipsychotics. The objective of this study was to assess the affinity of some atypical antipsychotic drugs in vitro for P-gp as indicative of their potential as P-gp substrates in vivo. The activity of P-gp towards four atypical and two conventional antipsychotics and a proven substrate, verapamil, was examined by their P-gp ATPase activity, a putative measure of P-gp affinity. The Michaelis-Menten equation was fitted to the data. The rank order of the ratio V(max) / K(m) was: verapamil (2.6) > quetiapine (1.7) > risperidone (1.4) > olanzapine (0.8) > chlorpromzaine (0.7) > haloperidol (0.3) = clozapine (0.3). The atypical antipsychotics quetiapine and risperidone were relatively good P-gp substrates, although their affinities were not as high as verapamil. Olanzapine showed intermediate affinity and clozapine showed the least affinity of the drugs studied. These results suggest that P-gp is likely to influence the access to the brain of all of the atypical antipsychotics studied to various degrees. In vivo studies are needed to confirm these findings.
authors.affiliation: Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President Street, PO Box 250861, Charleston, SC 29425, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Boulton
authors.forename: C Lindsay
authors.initials: CL
authors.lastname: DeVane
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Liston
authors.forename: John S
authors.initials: JS
authors.lastname: Markowitz
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines; D001667:Binding, Competitive; D003024:Clozapine / Q000494:pharmacology; D003987:Dibenzothiazepines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D000069348:Quetiapine Fumarate; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D011994:Recombinant Proteins; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D010890:Pirenzepine; D003024:Clozapine; D018967:Risperidone; D000077152:Olanzapine