Document Detail

Concentration-dependent effects and intracellular accumulation of HIV protease inhibitors in cultured CD4 T cells and primary human lymphocytes.
MedLine Citation:
PMID:  20237075     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: The intracellular and plasma concentrations of HIV protease inhibitors (HPIs) vary widely in vivo. It is unclear whether there is a concentration-dependent effect of HPIs such that at increasing concentration they may either block their own efflux (leading to 'autoboosting') or influx (leading to saturability/decreased intracellular accumulation).
METHOD: The effects of various concentrations (0-30 microM) of lopinavir, saquinavir, ritonavir and atazanavir on the accumulation of [(14)C]lopinavir, [(3)H]saquinavir, [(3)H]ritonavir and [(3)H]atazanavir, respectively, were investigated in CEM(parental), CEM(VBL) [P-glycoprotein (ABCB1) overexpressing], CEM(E1000) (MRP1 overexpressing) and in peripheral blood mononuclear cells (PBMCs). We also investigated the effects of inhibitors of ABCB1/ABCG2 (tariquidar), ABCC (MK571) and ABCC1/2 (frusemide), singly and in combination with HPIs, on cellular accumulation.
RESULTS: In all the cell lines, with increasing concentration of lopinavir, saquinavir and ritonavir, there was a significant increase in the cellular accumulation of [(14)C]lopinavir, [(3)H]saquinavir and [(3)H]ritonavir. Tariquidar, MK571 and frusemide (alone and in combination with lopinavir, saquinavir and ritonavir) significantly increased the accumulation of [(14)C]lopinavir, [(3)H]saquinavir and [(3)H]ritonavir. Ritonavir (alone or in combination with tariquidar) decreased the intracellular accumulation of [(3)H]ritonavir in PBMCs. Atazanavir decreased the accumulation of [(3)H]atazanavir in a concentration-dependent manner in all of the cells tested.
CONCLUSIONS: There are complex and variable drug-specific rather than class-specific effects of the HPIs on their own accumulation.
Omar Janneh; Patrick G Bray; Elizabeth Jones; Christoph Wyen; Peter Chiba; David J Back; Saye H Khoo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-17
Journal Detail:
Title:  The Journal of antimicrobial chemotherapy     Volume:  65     ISSN:  1460-2091     ISO Abbreviation:  J. Antimicrob. Chemother.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-04-09     Completed Date:  2010-06-22     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  7513617     Medline TA:  J Antimicrob Chemother     Country:  England    
Other Details:
Languages:  eng     Pagination:  906-16     Citation Subset:  IM    
Department of Biomolecular and Sport Sciences, James Starley Building, Priory Street, Coventry University, Coventry CV1 5FB, UK.
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MeSH Terms
CD4-Positive T-Lymphocytes / drug effects*,  metabolism*
Cells, Cultured
HIV Protease Inhibitors / pharmacokinetics*
Staining and Labeling
Reg. No./Substance:
0/HIV Protease Inhibitors; 10028-17-8/Tritium

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