title: Effects of aripiprazole and its active metabolite dehydroaripiprazole on the activities of drug efflux transporters expressed both in the intestine and at the blood-brain barrier.
abstract: The inhibition potencies of aripiprazole and its active metabolite, dehydroaripiprazole, on the activities of human multidrug resistance protein 1 (MDR1/ABCB1; P-glycoprotein), breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4), that are drug efflux transporters expressed both in the intestine and at the blood-brain barrier (BBB), were investigated. Aripiprazole and dehydroapripiprazole showed relatively strong inhibitory effects on human MDR1 with IC(50) values of 1.2 and 1.3 µm in human MDR1-transfected Mardin-Darby canine kidney (MDCKII-MDR1) cells, respectively. The inhibition potencies of other atypical antipsychotics (risperidone, paliperidone, olanzapine and ziprasidone) for human MDR1 were also evaluated using the same in vitro experimental system and IC(50) values were more than 10-fold higher than those of the two compounds. Aripiprazole and dehydroaripiprazole also had inhibition potencies against human BCRP with IC(50) values of 3.5 and 0.52 µm, respectively. The ratios of steady-state unbound concentrations of aripiprazole and dehydroaripiprazole to their IC(50) values against human MDR1 and BCRP activities were less than 0.1, whereas the theoretically maximum gastrointestinal concentration of aripiprazole ([I](2) ) to its IC(50) values was much higher than the cut-off value of 10, proposed by the International Transporter Consortium (ITC) and the Food and Drug Administration (FDA). In contrast, aripiprazole and dehydroaripiprazole showed almost no inhibitory effect against the activity of human MRP4. These findings indicate that aripiprazole is unlikely to cause drug-drug interactions (DDIs) at the BBB when co-administered with substrate drugs of these drug transporters investigated. However, interactions at the intestinal absorption process may be of concern.
authors: Drug Metabolism Research Laboratories, Astellas Pharma Inc., Kashima, Osaka, Japan. yasuhisa.nagasaka@astellas.com
authors: Yasuhisa
authors: Y
authors: Nagasaka
authors: Kazuo
authors: K
authors: Oda
authors: Takafumi
authors: T
authors: Iwatsubo
authors: Akio
authors: A
authors: Kawamura
authors: Takashi
authors: T
authors: Usui
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D000068180:Aripiprazole; D001711:Biotransformation; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D004077:Digoxin / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D061985:Madin Darby Canine Kidney Cells; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010539:Permeability; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D015363:Quinolones / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D004077:Digoxin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D010879:Piperazines; D015363:Quinolones; C513055:ABCB1 protein, human; C073492:ABCC4 protein, human; C116614:ABCG2 protein, human