Journal ArticleDOI
An examination of IC50 and IC50-shift experiments in assessing time-dependent inhibition of CYP3A4, CYP2D6 and CYP2C9 in human liver microsomes.
Loren Berry,Zhiyang Zhao +1 more
TLDR
The relationship between time-dependent inactivation (TDI) and IC50 is examined using a consolidated method for evaluating CYP450 inhibition during drug discovery and the "shifted IC50" could be used to estimate, the K(I) and TDI potency ratio k(inact)/K( I) to within 2-fold in most cases.Abstract:
The relationship between time-dependent inactivation (TDI) and IC50 is examined using a consolidated method for evaluating CYP450 inhibition during drug discovery. An IC50 fold-shift of >1.5 indicated significant TDI potency. Further, the "shifted IC50" could be used to estimate, the K(I) and TDI potency ratio k(inact)/K(I) to within 2-fold in most cases.read more
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Journal ArticleDOI
The Conduct of in Vitro Studies to Address Time-Dependent Inhibition of Drug-Metabolizing Enzymes: A Perspective of the Pharmaceutical Research and Manufacturers of America
Scott W. Grimm,Heidi J. Einolf,Steven D. Hall,Kan He,Heng-Keang Lim,Kah-Hiing John Ling,Chuang Lu,Amin A. Nomeir,Eleanore Seibert,Konstantine W. Skordos,George Tonn,Robert Van Horn,Regina W. Wang,Y. Nancy Wong,Tian J. Yang,R. Scott Obach +15 more
TL;DR: A team of scientists from 16 pharmaceutical research organizations that are member companies of the Pharmaceutical Research and Manufacturers of America offer a discussion of the phenomenon of TDI with emphasis on the laboratory methods used in its measurement.
Journal ArticleDOI
A Perspective on the Kinetics of Covalent and Irreversible Inhibition.
TL;DR: It is proposed that the kinact/KI should be employed as a critical parameter to identify covalent inhibitors, interpret structure-activity relationships (SARs), translate activity from biochemical assays to the cell, and more accurately define selectivity.
Journal ArticleDOI
Mechanism-Based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure–Activity Relationships and Discovery Strategies To Mitigate Drug–Drug Interaction Risks
Suvi T. M. Orr,Sharon L. Ripp,T. Eric Ballard,Jaclyn Louise Henderson,Dennis O. Scott,R. Scott Obach,Hao Sun,Amit S. Kalgutkar +7 more
TL;DR: Structure−Activity Relationships and Discovery Strategies To Mitigate Drug−Drug Interaction Risks and Pharmacokinetics, Dynamics and Metabolism.
Journal ArticleDOI
Mechanism-based Inhibition: Deriving KI and kinact directly from Time-Dependent IC50 Values
TL;DR: In this paper, the authors derive a relation between potentially time-dependent IC(50) values and K(I), k(inact) parameters for different types of inhibition.
Journal ArticleDOI
Inhibition of CYP2C19 and CYP3A4 by Omeprazole Metabolites and Their Contribution to Drug-Drug Interactions
TL;DR: Results of this study show that, although metabolites contribute to in vivo DDIs, their relative abundance in circulation or logP values do not predict their contribution to in vitro DDI risk.