RT Journal Article
SR Electronic
T1 Complex Cytochrome P450 Kinetics Due to Multisubstrate Binding and Sequential Metabolism. Part 1. Theoretical Considerations
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1090
OP 1099
DO 10.1124/dmd.121.000553
VO 49
IS 12
A1 Wang, Zeyuan
A1 Paragas, Erickson M.
A1 Nagar, Swati
A1 Korzekwa, Ken
YR 2021
UL http://dmd.aspetjournals.org/content/49/12/1090.abstract
AB Complexities in P450-mediated metabolism kinetics include multisubstrate binding, multiple-product formation, and sequential metabolism. Saturation curves and intrinsic clearances were simulated for single-substrate and multisubstrate models using derived velocity equations and numerical solutions of ordinary differential equations (ODEs). Multisubstrate models focused on sigmoidal kinetics because of their dramatic impact on clearance predictions. These models were combined with multiple-product formation and sequential metabolism, and simulations were performed with random error. Use of single-substrate models to characterize multisubstrate data can result in inaccurate kinetic parameters and poor clearance predictions. Comparing results for use of standard velocity equations with ODEs clearly shows that ODEs are more versatile and provide better parameter estimates. It would be difficult to derive concentration-velocity relationships for complex models, but these relationships can be easily modeled using numerical methods and ODEs.SIGNIFICANCE STATEMENT The impact of multisubstrate binding, multiple-product formation, and sequential metabolism on the P450 kinetics was investigated. Numerical methods are capable of characterizing complicated P450 kinetics.