In Vitro Experimental Models for Studying Drug Biotransformation

Abstract

Metabolism plays a cardinal role in determining the efficacy and safety of a new chemical entity (NCE). Too fast or too slow metabolism of an NCE can lead to lack of efficacy or severe adverse events. An NCE can sometimes either inhibit or induce the activity of the enzyme responsible for its metabolism. Inhibition of an enzyme can lead to a sudden, unexpected increase in exposure of the culprit NCE or of another coadministered compound, cleared by the enzyme whose activity is inhibited. Induction can lead to sudden increase in clearance of the NCE or in the formation of an undesirable metabolite. The evaluation of enzyme inhibition and induction together is part of drug–drug interaction (DDI) risk, so named because, in most cases, the enzyme inhibition or induction caused by one NCE affects the exposure, efficacy, and safety of another coadministered drug. Numerous in vitro tools address various aspects of metabolism — metabolic stability, metabolite/reactive intermediate (RI) formation, enzyme inhibition, enzyme induction — and integrate all this into evaluating a DDI risk for an NCE. This article aims to summarize the most commonly used current in vitro ADME (absorption, distribution, metabolism, and excretion) tools, used in drug discovery and development to best understand the metabolism of an NCE for its safe and efficacious use in humans. Keywords: absorption; ADME; in vitro; in vivo; disposition; metabolism; clearance; pharmacokinetics; drug–drug interactions; pharmacokinetics mass spectrometry