Prediction of Pharmacokinetics and Drug–Drug Interactions When Hepatic Transporters are Involved

摘要: Hepatobiliary transport mechanisms have been identified to play a significant role in determining the systemic clearance for number of widely prescribed drugs and an increasing new molecular entities (NMEs). While pharmacokinetics, drug transporters also regulate target tissue exposure key regulating pharmacological and/or toxicological responses. Consequently, it is great relevance discovery development assess hepatic transporter activity regard pharmacokinetic dose predictions evaluate variability associated with drug–drug interactions (DDIs) genetic variants. Mechanistic utilizing physiological-based modeling are increasingly used contribution delineate transporter–enzyme interplay on basis hypothesis-driven functional vitro findings. Significant strides were made techniques facilitate characterization hepatobiliary transport. However, challenges exist quantitative vitro–in vivo extrapolation kinetics due lack information absolute abundance both situations, differential function holistic reagents such as suspended plated hepatocytes systems, complete mechanistic understanding liver model structure. On other hand, models predict transporter-mediated DDIs range from basic static dynamic models. provide conservative estimates useful upfront avoiding false negative predictions, integrate multiple victim perpetrator parameters expected predictions. The aim this paper review current state model-based approaches clinical pharmacokinetics or NMEs that substrates transporters.