Drug Binding to Plasma Proteins

ALAN TALEVI; CAROLINA L. BELLERA

The ADME Encyclopedia. A Comprehensive Guide on Biopharmacy and Pharmacokinetics

Springer Nature

Año: 2022; p. 315 - 326

After absorption, most drugs will distribute heterogeneously across tissues and organs [1], with the total drug concentration in plasma generally not being representative of the total concentration in other tissues. The main factors that explain the non-homogeneous distribution are the affinity of the drug for drug transporters and/or for tissue constituents. In plasma, drug molecules can reversibly interact with plasma proteins (mainly albumin, α1-acid glycoprotein (AAG), and, to a lesser extent, lipoproteins). Due to its size, the complex between the drug and a plasma protein cannot readily leave the intravascular space through transcellular diffusion across the endothelia. The free drug theory assumes that only the unbound drug fraction freely permeates through biological barriers, directly contributing to drug distribution: if certain assumptions are met (e.g., absence of active transport), only unbound drug concentrations will be equal at steady state [2, 3]. Strictly speaking, though, significant extravasation of albumin to the interstitial space does occur, either through bulk fluid filtration or transcytosis [4, 5]; albumin returns to the intravascular space via lymph drainage, thus maintaining its concentration gradient across the capillary wall.Also according to the free drug theory, only unbound drug molecules can engage in complexation with the drug target(s). Therefore, non-specific binding to tissue elements will directly impact on the fraction of the dose available to exert the pharmacodynamic effect, and relatively high doses are commonly administered to compensate non-specific distribution and attain effective unbound drug levels at the site of action (in pseudo-equilibrium with the bound concentrations across the different body compartments). As discussed later in this chapter, binding to plasma proteins influences renal and, sometimes, hepatic clearance, and the apparent volume of distribution (Vd) of the drug. In turn, clearance (CL) and Vd are the key determinants of the elimination half-life of a drug (t1/2) [6]. It is thus clear that protein binding will have a direct impact on drug pharmacokinetics and pharmacodynamics. Though rarely relevant from a clinical perspective, drugs bound to plasma proteins are potentially subject to drug interactions involving displacement from their binding partner(s). Variations in the concentration of the binding partner(s) due to physiological and pathological states can also potentially have pharmacological consequences