ATAZANAVIR: EFFECTS ON P-GLYCOPROTEIN TRANSPORT AND CYP3A METABOLISM IN VITRO
作者： Elke S. Perloff , Su X. Duan , Paul R. Skolnik , David J. Greenblatt , Lisa L. von Moltke
关键词: Hydroxylation 、 Atazanavir Sulfate 、 Dose–response relationship 、 Pharmacology 、 Biology 、 Rhodamine 123 、 Enzyme inhibitor 、 In vivo 、 Atazanavir 、 Microsome
摘要: The effect of atazanavir on P-glycoprotein (P-gp) expression and activity, as well its inhibitory potency against CYP3A was evaluated in vitro. Induction P-gp activity studied using LS180V cells. inhibition both cells Caco-2 assessed by measuring P-gp-mediated rhodamine 123 (Rh123) transport, determined SDS-polyacrylamide gel electrophoresis/Western blot analysis. tested triazolam hydroxylation human liver microsomes (HLM). Extended (3-day) exposure to 30 μM caused a 2.5-fold increase immunoreactive concentration-dependent decrease intracellular Rh123 mean 45% (S.D. 5.2%) control. Acute (2 h) increased concentrations up 300% control at 100 atazanavir. At above, acute reversed induction 3-day pretreatment with 10 ritonavir. also observed cells, causing an comparable that for the known inhibitor verapamil (50% control). In HLM, hydroxylation, greatly preincubation. IC 50 values without preincubation were 0.31 0.13) 5.7 4.1), respectively. Thus, is inducer potent vitro, suggesting potential cause drug-drug interactions vivo.
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