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A numerical method for analysis of in vitro time-dependent inhibition data. Part 2. Application to experimental data

Korzekwa, Ken and Tweedie, Donald and Argikar, Upendra and Whitcher-Johnstone, Andrea and Bickford, Shari and Bell, Leslie and Nagar, Swati (2014) A numerical method for analysis of in vitro time-dependent inhibition data. Part 2. Application to experimental data. Drug Metabolism and Disposition.

Abstract

Time dependent inactivation (TDI) of cytochromes P450 (CYPs) is an important cause of drug-drug interactions (DDIs). The standard approach to characterize the kinetics of TDI is to determine the rate of enzyme loss, kobs, at various inhibitor concentrations, [I], and replot the kobs versus [I] to obtain KI and kinact. In Part 1, we used simulated datasets to develop and test a new numerical method to analyze in vitro TDI data. Here, we have applied this numerical method to 5 TDI datasets. Experimental datasets include the inactivation of CYP2B6, CYP2C8, and CYP3A4. None of the datasets exhibited MM-only kinetics, and the numerical method allowed use of more complex models to fit each dataset. Quasi-irreversible as well as partial inhibition kinetics were observed and parameterized. Three datasets required the use of an EII (multi-inhibitor binding) model. The mechanistic and clinical implications provided by these analyses are discussed. Together with the results in Part 1, we have developed and applied a new numerical method for analysis of in vitro TDI data. This method needs to be further validated with in vivo data.

Item Type: Article
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/21242

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