Single concentration loss of activity assay provides an improved assessment of drug-drug interaction risk compared to IC50-shift.
Xenobiotica
; 46(11): 953-66, 2016 Nov.
Article
em En
| MEDLINE
| ID: mdl-26956546
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Bioensaio
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Concentração Inibidora 50
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Interações Medicamentosas
Tipo de estudo:
Etiology_studies
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Prognostic_studies
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Risk_factors_studies
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article