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Xenobiotica
the fate of foreign compounds in biological systems
Volume 46, 2016 - Issue 11
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General Xenobiochemistry

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

, &
Pages 953-966 | Received 30 Oct 2015, Accepted 13 Jan 2016, Published online: 09 Mar 2016
 

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 (R2  = 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)) (R2 = 0.61) and the fold-shift in IC50 (R2 = 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.

Acknowledgments

The authors thank Larry Wienkers for helpful discussion and comments.

Declaration of interest

The authors report no conflicts of interest.

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