Michaelis-Menten from an In Vivo Perspective: Open Versus Closed Systems

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Biochemical Kinetics
• Systems Biology

Background:

• The Michaelis-Menten equation is a cornerstone of enzyme kinetics but often assumes a constant enzyme pool.
• In vivo drug metabolism studies frequently show deviations from in vitro data, especially with chronic drug administration.
• Enzyme induction or inhibition and changes in enzyme load can occur during chronic treatments.

Purpose of the Study:

• To re-evaluate the Michaelis-Menten system by incorporating enzymatic turnover (synthesis and elimination).
• To develop a more mechanistic model for substrate, free enzyme, and substrate-enzyme complex concentrations in vivo.
• To address limitations in predicting in vivo drug behavior from in vitro data and interspecies extrapolations.

Main Methods:

• Incorporation of enzyme synthesis and elimination rates into the Michaelis-Menten framework.
• Development of a new mathematical model for open systems with enzyme turnover.
• Analysis of substrate concentration dynamics under chronic dosing scenarios.

Main Results:

• In open systems with enzyme turnover, substrate concentration does not continuously rise beyond a certain chronic dosing threshold.
• Slow enzyme turnover leads to a linear relationship between substrate concentration and dose rate after an initial adjustment period.
• The derived model offers improved mechanistic insights into in vivo substrate and enzyme dynamics.

Conclusions:

• Enzyme turnover is a critical factor for accurate in vivo pharmacokinetic modeling, especially for chronic drug administration.
• The new open framework reconciles discrepancies between in vitro and in vivo data and improves interspecies extrapolation.
• This approach is also applicable to understanding transporter system kinetics.