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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
Author(s) -
Nagasaka Yasuhisa,
Oda Kazuo,
Iwatsubo Takafumi,
Kawamura Akio,
Usui Takashi
Publication year - 2012
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.1801
Subject(s) - aripiprazole , abcg2 , pharmacology , probenecid , chemistry , active metabolite , efflux , p glycoprotein , metabolite , transporter , drug , pharmacokinetics , atp binding cassette transporter , multiple drug resistance , biology , medicine , biochemistry , schizophrenia (object oriented programming) , gene , psychiatry , antibiotics
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 µ m 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 µ m , 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. Copyright © 2012 John Wiley & Sons, Ltd.