Cargando…

Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity

BACKGROUND: Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involve...

Descripción completa

Detalles Bibliográficos
Autores principales: Rijpma, Sanna R, van den Heuvel, Jeroen JMW, van der Velden, Maarten, Sauerwein, Robert W, Russel, Frans GM, Koenderink, Jan B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172838/
https://www.ncbi.nlm.nih.gov/pubmed/25218605
http://dx.doi.org/10.1186/1475-2875-13-359
_version_ 1782336081715265536
author Rijpma, Sanna R
van den Heuvel, Jeroen JMW
van der Velden, Maarten
Sauerwein, Robert W
Russel, Frans GM
Koenderink, Jan B
author_facet Rijpma, Sanna R
van den Heuvel, Jeroen JMW
van der Velden, Maarten
Sauerwein, Robert W
Russel, Frans GM
Koenderink, Jan B
author_sort Rijpma, Sanna R
collection PubMed
description BACKGROUND: Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involved in drug deposition, as they are located at membranes of many uptake and excretory organs and at protective barriers, where they export endogenous and xenobiotic compounds, including pharmaceuticals. In this study, a panel of well-established anti-malarial drugs which may affect drug plasma concentrations was tested for interactions with human ABC transport proteins. METHODS: The interaction of chloroquine, quinine, artemisinin, mefloquine, lumefantrine, atovaquone, dihydroartemisinin and proguanil, with transport activity of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP) and multidrug resistance-associated proteins (MRP) 1–4 were analysed. The effect of the anti-malarials on the ATP-dependent uptake of radio-labelled substrates was measured in membrane vesicles isolated from HEK293 cells overexpressing the ABC transport proteins. RESULTS: A strong and previously undescribed inhibition of BCRP-mediated transport by atovaquone with a 50% inhibitory concentration (IC(50)) of 0.23 μM (95% CI 0.17-0.29 μM) and inhibition of P-gp-mediated transport by quinine with an IC(50) of 6.8 μM (95% CI 5.9-7.8 μM) was observed. Furthermore, chloroquine and mefloquine were found to significantly inhibit P-gp-mediated transport. BCRP transport activity was significantly inhibited by all anti-malarials tested, whereas BSEP-mediated transport was not inhibited by any of the compounds. Both MRP1- and MRP3-mediated transport were significantly inhibited by mefloquine. CONCLUSIONS: Atovaquone and quinine significantly inhibit BCRP- and P-gp- mediated transport at concentrations within the clinically relevant prophylactic and therapeutic range. Co-administration of these established anti-malarials with drugs that are BCRP or P-gp substrates may potentially lead to drug-drug interactions.
format Online
Article
Text
id pubmed-4172838
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-41728382014-09-25 Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity Rijpma, Sanna R van den Heuvel, Jeroen JMW van der Velden, Maarten Sauerwein, Robert W Russel, Frans GM Koenderink, Jan B Malar J Research BACKGROUND: Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involved in drug deposition, as they are located at membranes of many uptake and excretory organs and at protective barriers, where they export endogenous and xenobiotic compounds, including pharmaceuticals. In this study, a panel of well-established anti-malarial drugs which may affect drug plasma concentrations was tested for interactions with human ABC transport proteins. METHODS: The interaction of chloroquine, quinine, artemisinin, mefloquine, lumefantrine, atovaquone, dihydroartemisinin and proguanil, with transport activity of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP) and multidrug resistance-associated proteins (MRP) 1–4 were analysed. The effect of the anti-malarials on the ATP-dependent uptake of radio-labelled substrates was measured in membrane vesicles isolated from HEK293 cells overexpressing the ABC transport proteins. RESULTS: A strong and previously undescribed inhibition of BCRP-mediated transport by atovaquone with a 50% inhibitory concentration (IC(50)) of 0.23 μM (95% CI 0.17-0.29 μM) and inhibition of P-gp-mediated transport by quinine with an IC(50) of 6.8 μM (95% CI 5.9-7.8 μM) was observed. Furthermore, chloroquine and mefloquine were found to significantly inhibit P-gp-mediated transport. BCRP transport activity was significantly inhibited by all anti-malarials tested, whereas BSEP-mediated transport was not inhibited by any of the compounds. Both MRP1- and MRP3-mediated transport were significantly inhibited by mefloquine. CONCLUSIONS: Atovaquone and quinine significantly inhibit BCRP- and P-gp- mediated transport at concentrations within the clinically relevant prophylactic and therapeutic range. Co-administration of these established anti-malarials with drugs that are BCRP or P-gp substrates may potentially lead to drug-drug interactions. BioMed Central 2014-09-13 /pmc/articles/PMC4172838/ /pubmed/25218605 http://dx.doi.org/10.1186/1475-2875-13-359 Text en © Rijpma et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Rijpma, Sanna R
van den Heuvel, Jeroen JMW
van der Velden, Maarten
Sauerwein, Robert W
Russel, Frans GM
Koenderink, Jan B
Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity
title Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity
title_full Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity
title_fullStr Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity
title_full_unstemmed Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity
title_short Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity
title_sort atovaquone and quinine anti-malarials inhibit atp binding cassette transporter activity
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172838/
https://www.ncbi.nlm.nih.gov/pubmed/25218605
http://dx.doi.org/10.1186/1475-2875-13-359
work_keys_str_mv AT rijpmasannar atovaquoneandquinineantimalarialsinhibitatpbindingcassettetransporteractivity
AT vandenheuveljeroenjmw atovaquoneandquinineantimalarialsinhibitatpbindingcassettetransporteractivity
AT vanderveldenmaarten atovaquoneandquinineantimalarialsinhibitatpbindingcassettetransporteractivity
AT sauerweinrobertw atovaquoneandquinineantimalarialsinhibitatpbindingcassettetransporteractivity
AT russelfransgm atovaquoneandquinineantimalarialsinhibitatpbindingcassettetransporteractivity
AT koenderinkjanb atovaquoneandquinineantimalarialsinhibitatpbindingcassettetransporteractivity