Medicine in Drug Discovery (Jun 2022)
Metabolism-mediated drug–drug interactions – Study design, data analysis, and implications for in vitro evaluations
Abstract
Therapeutics undergo metabolism as a major biotransformation pathway for their bioactivation or clearance from the body, which is a well-known factor for affecting drug pharmacokinetics, safety and efficacy. Drug metabolism primarily occurs in the liver and intestine, where expressing a wide variety of drug metabolizing enzymes, which are generally divided into Phase I enzymes like cytochrome P450s (CYP450s) and Phase II enzymes as UDP glucuronosyltransferases (UGTs). The chemical structures of therapeutic molecules are modified, which are called metabolites, as outcome of oxidation or conjugation by metabolism or biotransformation. Therefore, metabolism-mediated drug–drug interactions (MMDDI) may have more potential clinical significance than transporter-mediated drug–drug interactions (TMDDI), because both parent molecules and metabolites may contribute to the drug–drug interaction which may make the clinical significance more complicated. This article reviewed the challenges of MMDDI during therapeutic innovations, and industry solutions for supporting IND/NDA submissions according to the related guidances by the regulatory agencies as NMPA, FDA, PMDA and EMA.
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