TY - JOUR 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 DO - 10.1124/dmd.121.000553 SP - DMD-AR-2021-000553 AU - Zeyuan Wang AU - Erickson M. Paragas AU - Swati Nagar AU - Ken Korzekwa Y1 - 2021/01/01 UR - http://dmd.aspetjournals.org/content/early/2021/09/09/dmd.121.000553.abstract N2 - Complexities in CYP 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 due to 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 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 CYP kinetics was investigated. Numerical methods are capable of characterizing complicated CYP kinetics. ER -