title: P-glycoprotein interaction with risperidone and 9-OH-risperidone studied in vitro, in knock-out mice and in drug-drug interaction experiments.
abstract: The drug transporter P-glycoprotein (P-gp) influences drug distribution across the blood-brain barrier (BBB) by actively extruding drugs into the neural capillaries. Several psychotropic drugs, including nortriptyline (NT) and risperidone (Risp), are substrates of P-gp. Here we compared the in vitro P-gp interactions of Risp and its major metabolite, 9-OH-Risperidone (OH-Risp), with their distribution over the BBB in P-gp knock-out mice and in rats where P-gp was inhibited. K(m) and V(max) were determined by an in vitro ATPase assay, and V(max)/K(m) ratios of 2.7 and 0.5 were recorded for Risp and OH-Risp, respectively, suggesting that Risp is a better substrate for P-gp than OH-Risp. In Mdr1a (-/-) knock-out mice, the brain-serum ratios of both Risp and OH-Risp were more than ten times those of control mice (14 and 11, respectively). When P-gp was inhibited with cyclosporine A (CsA) in Wistar rats, the effect was an order of magnitude less than that observed for the knock-out mice experiments (1-1.5 times the controls), and co-administration of NT had no effect. In conclusion, both Risp and OH-Risp interact with P-gp in vitro, and P-gp has a profound effect on Risp and OH-Risp distribution over the BBB, as is evident from the knock-out mice experiments. Drug-drug interaction effects in relation to P-gp, however, appear to be more limited.
authors.affiliation: The Centre for Basic Psychiatric Research, Psychiatric Hospital in Aarhus, Denmark. tbe@psykiatri.aaa.dk
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Ejsing
authors.forename: Anne D
authors.initials: AD
authors.lastname: Pedersen
authors.forename: Kristian
authors.initials: K
authors.lastname: Linnet
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D009661:Nortriptyline / Q000494:pharmacology; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000929:Antidepressive Agents, Tricyclic; D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D016572:Cyclosporine; D000255:Adenosine Triphosphate; C095122:multidrug resistance protein 3; D009661:Nortriptyline; D000251:Adenosine Triphosphatases; D000068882:Paliperidone Palmitate