Antipsychotic drugs inhibit the function of breast cancer resistance protein.
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 microM) > risperidone (38.1 microM) > clozapine (42.0 microM) > paliperidone (51 microM) > chlorpromazine (52.2 microM) > quetiapine (66.1 microM) > olanzapine = haloperidol (>100.0 microM). 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 microM 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.
Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA. junsheng.wang@bms.com
Jun-Sheng
JS
Wang
Hao-Jie
HJ
Zhu
John S
JS
Markowitz
Jennifer L
JL
Donovan
Hong-Jie
HJ
Yuan
C Lindsay
CL
Devane
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000502:physiology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004970:Estrone / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005434:Flow Cytometry; D006801:Humans; D008658:Inactivation, Metabolic; D008942:Mitoxantrone / Q000493:pharmacokinetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013379:Substrate Specificity
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D014150:Antipsychotic Agents; D009363:Neoplasm Proteins; D004970:Estrone; D008942:Mitoxantrone; C017296:estrone sulfate