Enzyme induction: translating multiple approaches, assays, endpoints, and opinions into a valuable induction screening strategy.
Drug metabolizing enzyme induction, or the process of generating excess drug metabolizing enzyme in important tissues of drug disposition such as liver and intestine, can give rise to pharmacokinetic situations whereby drug interactions occur. There are two major concerns associated with enzyme induction. First is the potential loss of efficacy due to more rapid metabolism and second is the risk of an increase in the formation of a potential reactive/toxic metabolite. Because of this, pharmaceutical companies consider enzyme induction as an undesired drug property for their potential drug candidates. As a consequence, the number of tools and models to evaluate induction of drug metabolizing enzymes has been increased tremendously over the past decade. As often is the case, every assay and approach has its own advantages and disadvantages and unfortunately, no single tool is currently available to predict the induction potential of drug candidates in humans. The purpose of this review is not only to outline the screening tools currently available for determining the induction potential of new chemical entities but also to translate these tools into a valuable screening strategy, covering aspects such as, induction liability assessment, structure-activity relationships (SAR), induction risk assessment and translating in vitro findings into clinical relevance.
Fretland
Adrian
A
Hoffmann-La Roche, Drug Metabolism & Pharmacokinetics, 340 Kingsland Street, Nutley, NJ 07110-1199, USA.
Monshouwer
Mario
M
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D010600:Pharmacology