Redefining the Michaelis-Menten Kinetics Mechanistic Basis and Derivation in Drug Metabolism, Pharmacology, Biochemistry, Chemistry, and Pharmacokinetics

Since the recognition of chemical rates of reaction 175 years ago, all derivations of rate constants in drug metabolism, pharmacology, biochemistry, chemistry, as well as clearance values in pharmacokinetics and clinical medicine, require solving differential equations based on mechanistic hypotheses at steady-state. This approach leads to mostly consistent, but not always, operational results for linear systems but introduces numerous ambiguities, and un-necessary and unsupported quasi-steady-state assumptions for nonlinear systems. Yet, thousands of papers and all textbooks describing kinetics in drug metabolism, pharmacology, biochemistry, and pharmacokinetics accept these assumptions. We demonstrate that correctly combining parallel and in series rate-defining kinetic processes enables simple derivation for both in vitro and in vivo linear and here, Michaelis-Menten nonlinear systems. Using this new methodology we derive the Michaelis-Menten equation requiring no assumption regarding (a) the mechanism of the substrate-enzyme interaction, (b) steady-state or quasi-steady-state believed necessary to solve the differential equations first presented 100 years ago, (c) the ratio of enzyme-to-substrate concentrations, (d) the order and (e) reversibility (or lack of reversibility) of the enzyme-substrate complex. We demonstrate that the new methodology gives the same outcome as the traditional differential equation derivation for the in vivo impact of hepatic blood flow for high clearance compounds, e.g., ethanol. The proposed methodology is independent of differential equations and mechanistic constraints, is applicable to all linear and nonlinear kinetic processes in vitro and in vivo , greatly simplifying characterization and teaching of kinetic concepts.