Biomolecules & Therapeutics : eISSN 2005-4483 / pISSN 1976-9148

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Fig. 9. Boundary line for kobs for time-dependent inhibition and relation to in vivo drug-drug interactions (DDI) (Eng et al., 2021). (A) Fifty drugs were evaluated for P450 3A4 time-dependent inhibition in human liver microsomes (at 30 µM unless noted otherwise) and ranked by kobs, the first-order rate of inactivation, as judged using midazolam 1´-hydroxylation (⃝), presented on a log10 scale (right y-axis). The filled bars show the in vivo drug-drug interactions as judged by the AUCR (AUC with the drug divided by the AUC without the drug, Clinical DDI magnitude). (B) The study in Part A was repeated in human hepatocytes. The stippled line indicates a 2-fold in vivo difference. Also indicated are p<0.05 statistical limits and a kobs “boundary” of the lowest in vitro value with 2-fold in vivo difference. Reprinted from Drug Metab. Dispos., Vol. 49, Eng, H., Tseng, E., Cerny, M. A., Goosen, T. C. and Obach, R. S., Cytochrome P450 3A time-dependent inhibition assays are too sensitive for identification of drugs causing clinically significant drug-drug interactions: a comparison of human liver microsomes and hepatocytes and definition of boundaries for inactivation rate constants, pages 442-450 (Eng et al., 2021), Copyright (2021), with permission from American Society for Pharmacology and Experimental Therapeutics.
Biomolecules & Therapeutics 2022;30:1~18
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