Advances in methodologies for predicting metabolic stability for low-clearance drugs / 中国药科大学学报

@#The metabolic stability test of drugs is a key step in drug discovery and achieving low clearance is frequently the goal in the design of drug. Increased drug metabolism stability can reduce drug dosage, enhance drug exposure and prolong drug half-life. Accurately assessing the metabolic stability parameters of low clearance drugs and predicting human pharmacokinetics has become a challenge. Traditional tools in vitro including microsomes and suspended primary hepatocytes are limited by incubation time, which is not long enough to make sufficient metabolic conversion. Determination of intrinsic clearance or metabolic pathways and mechanisms of drug are implicated. Novel models tend to further mimic the in vivo environment in order to prolong lifetime of hepatocytes and achieve sufficient metabolic turnover of drugs for monitoring. In vitro-in vivo correlation of intrinsic clearance of methodologies has evaluated to support the reliability in predicting human pharmacokinetics. Application of these methodologies greatly decreases the forthputting of experimental animals and the release of expensive clinical trials during the acquisition of pharmacokinetic parameters. In this review, we summarized the principles, advantages and disadvantages of the novel in vitro methodologies for metabolic stability dealing with low-turnover drugs, including hepatocyte relay method, plated human hepatocytes, coculture system and microfluidic devices. Future prospect is proposed for in vitro metabolic models and it provides reference and optimization in metabolic stability for early lead compounds.

Research progress of P-glycoprotein induction / 中国药科大学学报

P-glycoprotein(P-gp)is an important efflux protein of ATP-binding cassette transporter superfamily. Cells could be protected from detrimental xenobiotics by the up-regulation of efflux pumps.In this review, an extensive literature search for P-gp induction research was conducted, and a focus was brought onto the P-gp induction models,experiment methods and its applications in drug discovery.We mainly introduced the in vitro cell-based models and in vivo rodent animal models for induction research, methods that investigate induction potency by detecting the protein,gene expression and efflux function,as well as co-regulation between P-gp and other transporters or drug metabolism enzymes.P-gp induction can serve as a clinical therapeutic strategy by reducing the intracellular concentration of deleterious xenobiotics significantly,and the in silico P-gp induction pharmacophore model was also discussed.This review could be of great importance for pre-clinical drug design, the screening of new synthesized compounds and the prediction of potential clinical drug-drug interactions.