The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery

Abstract

Data from in vitro plasma protein binding experiments that determine the fraction of protein-bound drug are frequently used in drug discovery to guide structure design and to prioritize compounds for in vivo studies. However, we consider that these practices are usually misleading, because in vivo efficacy is determined by the free (unbound) drug concentration surrounding the therapeutic target, not by the free drug fraction. These practices yield no enhancement of the in vivo free drug concentration. So, decisions based on free drug fraction could result in the wrong compounds being advanced through drug discovery programmes. This Perspective provides guidance on the application of plasma protein binding information in drug discovery.

Postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in rabbits over 24 h

“…Free drug concentration -In pharmacological studies the term "free" drug refers to the unbound drug concentration that not bound to plasma proteins [25]. However in postmortem studies involving morphine it is common to refer to free morphine as the concentration of unconjugated morphine quantitated with total morphine referring to the amount of "free" morphine and conjugated morphine.…”

Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835

“…All four compounds displayed satisfactory aqueous solubility and Caco-2 permeability, which confirmed the new chemotype was promising from further development prospective. The relatively high plasma protein binding observed for 4k-n perhaps is not surprising for these highly lipophilic compounds 22 and may not present a significant development obstacle provided the rate of dissociation from plasma proteins is sufficient to maintain the required plasma levels (vide infra). The principal weakness of the series studied herein was its low metabolic stability determined by incubation of compounds 4k-n in the presence of mouse liver microsomes.…”

Leveraging model-based study designs and serial micro-sampling techniques to understand the oral pharmacokinetics of the potent LTB4 inhibitor, CP-105696, for mouse pharmacology studies

“…All data presented here are total plasma concentrations. CP-105696 is known to be highly bound to plasma proteins (> 99% bound) (Showell et al, 1996, Liston et al, 1998 therefore, while high total concentrations are achieved, only a fraction is free and able to interact with its target (Smith et al, 2010).…”