Concentration-dependent effects and intracellular accumulation of HIV protease inhibitors in cultured CD4 T cells and primary human lymphocytes.
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).


METHODS
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.
Janneh
Omar
O
Department of Biomolecular and Sport Sciences, James Starley Building, Priory Street, Coventry University, Coventry CV1 5FB, UK.
Bray
Patrick G
PG
Jones
Elizabeth
E
Wyen
Christoph
C
Chiba
Peter
P
Back
David J
DJ
Khoo
Saye H
SH
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D013194:Staining and Labeling; D014316:Tritium
D017320:HIV Protease Inhibitors; D014316:Tritium