NDLI: Single concentration loss of activity assay provides an improved assessment of drug-drug interaction risk compared to IC50-shift.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Wong, Simon G. Lee, Mey Wong, Bradley K.
Description	Country affiliation: United States Author Affiliation: Wong SG ( a Department of Pharmacokinetics and Drug Metabolism , Amgen , South San Francisco , CA , USA.); Lee M ( a Department of Pharmacokinetics and Drug Metabolism , Amgen , South San Francisco , CA , USA.); Wong BK ( a Department of Pharmacokinetics and Drug Metabolism , Amgen , South San Francisco , CA , USA.)
Abstract	1. The utility of two abbreviated, higher-throughput assays [IC50-shift and the loss of activity (LOA) assay] to evaluate time-dependent inhibition (TDI) of 24 structurally related compounds was compared. 2. Good correlation (R(2) = 0.90) between % inhibition and kinact/KI suggested that the LOA assay has utility as an indicator of TDI potential. Weaker correlation was observed for the shifted IC50 (IC50(T = 30)) (R(2) = 0.61) and the fold-shift in IC50 (R(2) = 0.17). 3. Primary mechanism for poor correlation was depletion of active enzyme at concentrations > 1 µM leading to greater than predicted inhibition in the IC50-shift assay. 4. Previously reported strong correlations between IC50(T = 30) and kinact/KI were found to be dependent on potent TDI compounds with kinact/KI > 30; correlation was reduced for moderate inhibitors (kinact/KI < 30). LOA assay maintained good correlation even when strong TDI compounds were excluded. 5. LOA assay (% Inhibition at 30 min, 10 µM) was a good predictor of in vivo DDI (AUCr), providing a graded response with low potential for false negatives or positives. IC50-shift assay had bias for over-predicting in vivo DDI and was more likely to identify false positives.
File Format	HTM / HTML
ISSN	00498254
Issue Number	11
Journal	Xenobiotica
Volume Number	46
e-ISSN	13665928
Language	English
Publisher	Taylor & Francis
Publisher Date	2016-11-01
Publisher Place	Great Britain (UK)
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Discipline Toxicology
Content Type	Text
Resource Type	Article
Subject	Health, Toxicology and Mutagenesis Medicine Biochemistry Toxicology Pharmacology

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