LAUSR

The selection of an appropriate drug target, as well as a solid understanding of drug pharmacokinetics and pharmacodynamics, are crucial for successful drug discovery1. Although it is generally accepted that the free (unbound) concentration of a drug is the driving force for its pharmacological effects (as only free drug molecules are available to interact with the therapeutic target), there are several misconceptions regarding the impact of drug binding on pharmacokinetics2. It is important to understand that the binding of a drug to constituents of the blood or tissues does not alter the overall unbound drug concentration following chronic drug administration, as this is primarily determined by intrinsic clearance2. However, drug binding can highly influence the pharmacokinetic profile, owing to the effects on the volume of distribution (V) and total drug clearance (CL), which are based on measurements of the total plasma concentration. The major nonspecific drug-binding constituents are albumin (which is found in the blood and interstitial fluids) and acidic phospholipids (which are predominantly found in the tissues). Although drugs have only moderate affinity (potency) for these constituents, the impact of these constituents on drug pharmacokinetics is high because they are present at high concentrations. However, the impact of the drug binding to the target itself is often not discussed, although the affinity of drugs for their targets will often be much higher than the affinity of drugs for nonspecific blood and/or tissue constituents. Consequently, many small-molecule drug discovery projects are mounted with a firm biological rationale for the target, yet have little knowledge of the actual concentration of this protein, whether in the initial in vitro screens, in the subsequent in vivo animal studies, or in healthy subjects or patients. The potential consequences of this lack of knowledge can range from unreliable conclusions about compound potency to unusual and even highly variable pharmacokinetics in humans. In this article, we briefly highlight the underappreciated impact of target-mediated drug disposition (TMDD)3 on small-molecule drug discovery, as well as approaches to address this issue.