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Received for publication November 5, 2004.
Revised March 7, 2005.
Accepted for publication March 8, 2005.
The effect of atazanavir on P-glycoprotein expression and activity, as well as its inhibitory potency against CYP3A activity, was evaluated in vitro. Induction of P-gp activity and expression was studied using LS180V cells. P-gp inhibition was studied using both LS180V cells and Caco-2 cells. P-gp activity was assessed by measuring P-gp mediated rhodamine123 (Rh123) transport, and P-gp expression was determined using SDS-PAGE/western blot analysis. CYP3A inhibition was tested using triazolam hydroxylation in human liver microsomes (HLM). Extended (3-day) exposure of LS180V cells to 30 µM atazanavir caused a 2.5-fold increase in immunoreactive P-gp expression as well as a concentration-dependent decrease of intracellular Rh123 to a mean 45% (SD 5.2%) of control. Acute exposure (60 min) of LS180V cells to atazanavir increased intracellular Rh123 concentrations up to 300% of control at 100 µM atazanavir. At 30 µM and above, acute atazanavir exposure reversed P-gp induction caused by 3-day pre-treatment with 10 µM ritonavir. P-gp inhibition was also observed in Caco-2 cells, causing an effect comparable to that observed for the known P-gp inhibitor verapamil (50% of control). In HLM, atazanavir was an inhibitor of triazolam hydroxylation, with inhibitory potency greatly increased by preincubation. IC50 values with and without pre-incubation were 0.31 µM (SD 0.13) and 5.7 µM (SD 4.1), respectively. Thus atazanavir is an inhibitor and inducer of P-gp as well as a potent inhibitor of CYP3A in vitro, suggesting a potential for atazanavir to cause drug-drug interactions in vivo.
Key words:
CYP inhibition, CYP3A, drug disposition, drug transport, drug-drug interactions, mechanism-based inhibition, p-glycoprotein
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