Open AccessSuccessful and Unsuccessful Prediction of Human Hepatic Clearance for Lead Optimization
Author(s) -
Jasleen K. Sodhi,
Leslie Z. Benet
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01930
Subject(s) - in vivo , chemistry , bioavailability , pharmacokinetics , pharmacology , drug metabolism , in vitro , metabolic clearance rate , drug , clearance , biochemistry , medicine , biology , microbiology and biotechnology , urology
Development of new chemical entities is costly, time-consuming, and has a low success rate. Accurate prediction of pharmacokinetic properties is critical to progress compounds with favorable drug-like characteristics in lead optimization. Of particular importance is the prediction of hepatic clearance, which determines drug exposure and contributes to projection of dose, half-life, and bioavailability. The most commonly employed methodology to predict hepatic clearance is termed in vitro to in vivo extrapolation (IVIVE) that involves measuring drug metabolism in vitro , scaling-up this in vitro intrinsic clearance to a prediction of in vivo intrinsic clearance by reconciling the enzymatic content between the incubation and an average human liver, and applying a model of hepatic disposition to account for limitations of protein binding and blood flow to predict in vivo clearance. This manuscript reviews common in vitro techniques used to predict hepatic clearance as well as current challenges and recent theoretical advancements in IVIVE.