RT Journal Article
SR Electronic
T1 A Numerical Method for Analysis of In Vitro Time-Dependent Inhibition Data. Part 2. Application to Experimental Data
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1587
OP 1595
DO 10.1124/dmd.114.058297
VO 42
IS 9
A1 Ken Korzekwa
A1 Donald Tweedie
A1 Upendra A. Argikar
A1 Andrea Whitcher-Johnstone
A1 Leslie Bell
A1 Shari Bickford
A1 Swati Nagar
YR 2014
UL http://dmd.aspetjournals.org/content/42/9/1587.abstract
AB Time-dependent inhibition (TDI) of cytochrome P450 enzymes is an important cause of drug-drug interactions. 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 our companion manuscript (Part 1; Nagar et al., 2014) in this issue of Drug Metabolism and Disposition, 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 five TDI datasets. Experimental datasets include the inactivation of CYP2B6, CYP2C8, and CYP3A4. None of the datasets exhibited Michaelis-Menten–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 a multiple-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.