PHARMACOKINETIC CONSEQUENCES OF INDUCTION OF CYP2E1 BY LIGAND STABILIZATION

Models of the time course of the effect of P450 induction on substrate clearance have previously only considered induction through enhanced synthesis of protein. Induction of CYP2E1 does not always conform to t his model, in that many chemicals induce the enzyme through stabilizat ion of the protein apparently by binding to the active site. While suc h binding protects the enzyme from degradation, it also results in com petitive inhibition of substrate clearance. We present a model based o n experimental studies of chemical induction of CYP2E1 by ligand stabi lization through which this mechanism of induction can be translated i nto its pharmacokinetic consequence with regard to clearance of substr ate. CYP2E1 is considered to be localized in two pools: Pool 1 at whic h two mechanisms of degradation, fast and slow, operate and pool 2, at which only the slower mechanism operates. Binding of substrate to enz yme in pool 1 stabilizes it from degradation by the fast process, leav ing only the slow process. Ligand stabilization therefore results in i nduction of CYP2E1 as enzyme accumulates as a consequence of unchanged synthesis. Binding of ligand to the active site results in competitiv e inhibition of the clearance of substrate. Model-based computer simul ations show that the time course of interaction between inhibitor/indu cer and substrate can be predicted from knowledge of I/K-i and S/K-m a nd the synthesis and degradation kinetics of CYP2E1. The simulations d emonstrate further that as long as inhibitor/inducer administration is not interrupted, the clearance of substrate will always be less than the value observed at low concentration of substrate even if the subst rate concentration is raised to displace inhibitor/inducer from the ac tive site. On the other hand, the degree of inhibition of clearance is less than would be seen if induction had not taken place. Clearance o f substrate is observed to rise above the value observed in the absenc e of the inhibitor/inducer only after the inhibitor/inducer concentrat ion declines low enough for substrate to gain access to the active sit e of the enzyme. The model-based simulations agree with reports of the interaction between isoniazid and acetaminophen in humans.