PHARMACOKINETICS OF DRUGS THAT INACTIVATE METABOLIC ENZYMES

The pharmacokinetics of drugs that cause inactivation of metabolic enzymes were derived for the single-compartment model with linear elimination kinetics. A simple mechanism for suicide inactivation of enzyme by its substrate was used to model the relationship between elimination of drug and enzyme activity as a function of time. Three modes of administration were considered: a single bolus dose, repetitive bolus dosing, and continuous administration. Unlike capacity-limited drug elimination, a bolus dose would always give apparent linear kinetics. The apparent terminal half-life after a bolus dose was a simple function of the remaining elimination activity. Repetitive dosing would give a gradual increase in half-life until the steady-state elimination activity was achieved. The time to achieve steady-state drug levels with continuous administration of drug, or repetitive dosing, was prolonged by the enzyme inactivation process, and was dependent on the rates of elimination, enzyme inactivation, and the dosing rate. Interactions between drugs would occur due to a reduction in elimination activity if they share the inactivated enzyme pathway, and the magnitude of the effect would be characterized by the shift in the terminal half-life of elimination.