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J Antimicrob Chemother. 2010 May;65(5):906-16. doi: 10.1093/jac/dkq082. Epub 2010 Mar 17.

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

Author information

1
Department of Biomolecular and Sport Sciences, James Starley Building, Priory Street, Coventry University, Coventry CV1 5FB, UK.

Abstract

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.

PMID:
20237075
PMCID:
PMC2851493
DOI:
10.1093/jac/dkq082
[Indexed for MEDLINE]
Free PMC Article

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