JAC Advance Access originally published online on January 3, 2007
Journal of Antimicrobial Chemotherapy 2007 59(2):238-245; doi:10.1093/jac/dkl474
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Modulation of human BCRP (ABCG2) activity by anti-HIV drugs
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
Received 14 August 2006; returned 4 October 2006; revised 17 October 2006; accepted 29 October 2006
*Corresponding author. Tel: +49-6221-56-39402; Fax: +49-6221-56-4642; E-mail: johanna.weiss{at}med.uni-heidelberg.de
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
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Giri, N. Shaik, G. Pan, T. Terasaki, C. Mukai, S. Kitagaki, N. Miyakoshi, and W. F. Elmquist Investigation of the Role of Breast Cancer Resistance Protein (Bcrp/Abcg2) on Pharmacokinetics and Central Nervous System Penetration of Abacavir and Zidovudine in the Mouse Drug Metab. Dispos., August 1, 2008; 36(8): 1476 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shaik, N. Giri, G. Pan, and W. F. Elmquist P-glycoprotein-Mediated Active Efflux of the Anti-HIV1 Nucleoside Abacavir Limits Cellular Accumulation and Brain Distribution Drug Metab. Dispos., November 1, 2007; 35(11): 2076 - 2085. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. H. Storch, R. Ehehalt, W. E. Haefeli, and J. Weiss Localization of the Human Breast Cancer Resistance Protein (BCRP/ABCG2) in Lipid Rafts/Caveolae and Modulation of Its Activity by Cholesterol in Vitro J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 257 - 264. [Abstract] [Full Text] [PDF]
|
|