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Antipsychotic Drugs Inhibit the Function of Breast Cancer Resistance Protein
Author(s) -
Wang JunSheng,
Zhu HaoJie,
Markowitz John S.,
Donovan Jennifer L.,
Yuan HongJie,
DeVane C. Lindsay
Publication year - 2008
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2008.00298.x
Subject(s) - antipsychotic , pharmacology , breast cancer , medicine , function (biology) , chemistry , cancer , biology , schizophrenia (object oriented programming) , psychiatry , microbiology and biotechnology
The ABCG2 transporter breast cancer resistance protein (BCRP) has been identified in several physiological sites. It has been suggested to play an important role in disposition of many drugs and environmental toxins. We investigated the effects of several antipsychotic drugs, including risperidone, 9‐hydroxy‐risperidone (paliperidone), olanzapine, quetiapine, clozapine, haloperidol and chlorpromazine, and a positive control inhibitor Ko143 on functions of BCRP in MCF7 and BCRP over‐expressing MCF7/MX100 cell lines using a BCRP prototypical substrate mitoxantrone. Our findings indicated that the tested antipsychotics rank order of potency of inhibition of BCRP according to concentrations required to reach 50% of maximum inhibition (IC 50 ) was as follows: Ko143 (0.07 µM) > risperidone (38.1 µM) > clozapine (42.0 µM) > paliperidone (51 µM) > chlorpromazine (52.2 µM) > quetiapine (66.1 µM) > olanzapine = haloperidol (>100.0 µM). We further tested the effects of various concentrations of risperidone on the BCRP‐mediated transport of oestrone‐3‐sulfate in a colon carcinoma cell line, Caco‐2, a widely used model to study drug absorption. Our findings show that risperidone at concentrations ranging from 1 to 100 µM significantly inhibited intracellular accumulation of oestrone‐3‐sulfate in Caco‐2 cell monolayers. The present results suggest that a potential source of pharmacokinetic interactions exists between BCRP substrates and several antipsychotics.