title: Impact of genetic deficiencies of P-glycoprotein and breast cancer resistance protein on pharmacokinetics of aripiprazole and dehydroaripiprazole.
abstract: 1. We investigated how deficiencies in P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) affect the pharmacokinetics of atypical antipsychotics aripiprazole and its active metabolite (dehydroaripiprazole) using normal Friend leukemia virus strain B (FVB) mice, BCRP knockout (Bcrp[-/-]) mice, and P-gp and BCRP triple knockout (Mdr1a/1b[-/-]Bcrp[-/-]) mice. 2. While plasma concentrations of aripiprazole and dehydroaripiprazole after oral administration were slightly higher in both Bcrp(-/-) and Mdr1a/1b(-/-)/Bcrp(-/-) mice than in normal FVB mice, the difference was not marked. The increase in absolute bioavailability (F) compared with normal mice (approximately 1.3-fold increase) was comparable between Bcrp(-/-) and Mdr1a/1b(-/-)/Bcrp(-/-) mice. This finding suggests that BCRP may be involved in the intestinal absorption of aripiprazole in mice, albeit with minimal contribution to absorption at best. 3. In contrast, the brain-to-plasma concentration ratio (Kp,brain) for aripiprazole and dehydroaripiprazole after oral administration was significantly higher in Mdr1a/1b(-/-)/Bcrp(-/-) mice than in normal mice, whereas Bcrp(-/-) mice exhibited Kp,brain values similar to those in normal mice. In addition, the Kp,brain values in Mdr1a/1b(-/-)/Bcrp(-/-) mice were not drastically different from those previously reported in Mdr1a/1b(-/-) mice, suggesting that brain penetration of aripiprazole and dehydroaripiprazole can be affected by P-gp, but with little synergistic effect of BCRP.
authors.affiliation: Analysis and Pharmacokinetics Research Labs, Astellas Pharma Inc. , Ibaraki , Japan .
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Nagasaka
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Sano
authors.forename: Kazuo
authors.initials: K
authors.lastname: Oda
authors.forename: Akio
authors.initials: A
authors.lastname: Kawamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Usui
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics*; D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics*; D000068180:Aripiprazole; D001711:Biotransformation / Q000235:genetics; D001923:Brain Chemistry; D007275:Injections, Intravenous; D051379:Mice; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics*; D015363:Quinolones / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; C517414:dehydroaripiprazole; D000068180:Aripiprazole
keywords: Aripiprazole; P-glycoprotein; brain penetration; breast cancer resistance protein; dehydroaripiprazole; knockout mouse; mdr1a/1b; pharmacokinetics