Abstract
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.
Footnotes
- Received May 25, 2021.
- Accepted September 6, 2021.
This work was supported by National Institutes of Health National Institute of General Medical Sciences (to K.K. and S.N.) [Grants 2R01GM104178 and 2R01GM114369].
The authors have no financial disclosures, and no conflicts of interest to report.
↵1 Z.W. and E.M.P. contributed equally to the work.
↵
This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|