Figure 3. Michaelis-Menten kinetics and drug concentration in plasma over time under the condition of zero-order kinetics.

A. Michaelis-Menten kinetics. As the concentration of drug increases above zero, the velocity of the reaction (V, metabolism rate) increases. When the drug concentration is substantially smaller than Km (the drug concentration at half-maximal V), first-order kinetics apply (i.e., metabolism rate is proportional to drug concentration). At concentrations much larger than Km (i.e., at Vmax), zero-order kinetics occur (i.e., metabolism rate is constant and independent of drug concentration). At concentrations near Km, a transition from first- to zero-order will occur in vivo as plasma drug concentration increases, because first-order kinetics no longer apply. B. Transitional kinetics. When approaching saturation kinetics during maintenance therapy, the dose of drug taken during the dosing interval exceeds the ability to eliminate (e.g., metabolize) the dose within the dosing interval. This results in increasing plasma concentration of drug with time and a failure to attain a steady state (plateau). Ultimately, plasma drug concentration exceeds the threshold for toxicity, and an adverse reaction occurs.