Drug-Target Residence Time Affects <i>in Vivo</i> Target Occupancy through Multiple Pathways

Abstract

The drug discovery and development process is greatly hampered by difficulties in translating <i>in vitro</i> potency to <i>in vivo</i> efficacy. Recent studies suggest that the long-neglected drug-target residence time parameter complements classical drug affinity parameters (<i>K</i> _I, <i>K</i> _d, IC₅₀, or EC₅₀) and is a better predictor of <i>in vivo</i> efficacy. Compounds with a long drug-target residence time are often more efficacious <i>in vivo</i>. The impact, however, of the drug-target residence time on <i>in vivo</i> efficacy remains controversial due to difficulties in experimentally determining the <i>in vivo</i> target occupancy during drug treatment. To tackle this problem, an <i>in vivo</i> displacement assay was developed using soluble epoxide hydrolase as a biological model. In this report, we experimentally demonstrated that drug-target residence time affects the duration of <i>in vivo</i> drug-target binding. In addition, the drug-target residence time plays an important role in modulating the rate of drug metabolism which also affects the efficacy of the drug.