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A Numerical Method for Analysis of In Vitro Time-dependent Inhibition Data. Part 2. Application to Experimental Data

Korzekwa, K and Tweedie, DJ and Argikar, UA and Whitcher-Johnstone, A and Bell, L and Bickford, S and Nagar, S (2014) A Numerical Method for Analysis of In Vitro Time-dependent Inhibition Data. Part 2. Application to Experimental Data. Drug Metab Dispos .

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 the key kinetic parameters, 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 appears to be generally applicable to model in vitro TDI data with atypical and complex kinetic schemes

Item Type: Article
Additional Information: NIBR author: Leslie, B institute: NIBR contributor address:
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22595

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