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JAC Advance Access published online on January 3, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl474
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received August 14, 2006
Revised October 17, 2006
Accepted October 29, 2006

Original article

Modulation of human BCRP (ABCG2) activity by anti-HIV drugs

Johanna Weiss 1 *, Johanna Rose 1, Caroline Henrike Storch 1, Nahal Ketabi-Kiyanvash 1, Alexandra Sauer 1, Walter Emil Haefeli 1, and Thomas Efferth 2

1 Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
2 Department of Toxicology and Cancer Risk Factors, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany

* To whom correspondence should be addressed.
Johanna Weiss, E-mail: johanna.weiss{at}med.uni-heidelberg.de


  Abstract

Objectives: The safety and effectiveness of highly active antiretroviral therapy (HAART) is challenged by viral resistance to antiretrovirals and the frequent occurrence of drug interactions which may limit the access of these drugs to the target sites. In particular, drug distribution and elimination may be modified by active efflux transporters. While P-glycoprotein is well evaluated in this regard, the interaction of antiretrovirals with the ABC transporter BCRP (ABCG2) is far from being elucidated. The aim of this study was therefore to investigate the influence of all important anti-HIV drugs on BCRP activity in vitro in one assay to allow unrestricted comparison of the results.

Methods: BCRP inhibition was assessed by an increase in pheophorbide A accumulation in MDCKII-BCRP cells and compared with the corresponding parental cell line MDCKII lacking human BCRP.

Results: According to the IC50 estimation, the rank order for BCRP inhibition was lopinavir > nelfinavir > delavirdine > efavirenz > saquinavir > atazanavir > amprenavir > abacavir. Whereas nevirapine and zidovudine exerted weak inhibition, the inhibitory potency for ritonavir and tipranavir could not be estimated due to their low solubility and all other tested compounds (indinavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zalcitabine) were devoid of an effect.

Conclusions: Taken together, our study demonstrates significant inhibition of BCRP by many anti-HIV drugs. These results suggest that inhibition of BCRP might contribute to drug-drug interactions observed during HAART in vivo and possibly also the superior effectiveness of combination antiretroviral therapy.

Keywords: HIV-protease inhibitors; non-nucleoside reverse transcriptase inhibitors; nucleoside reverse transcriptase inhibitors; nucleotide reverse transcriptase inhibitors; drug interactions.
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