Drug Binding to Tissue Components

ALAN TALEVI; CAROLINA L. BELLERA

The ADME Encyclopedia. A Comprehensive Guide on Biopharmacy and Pharmacokinetics

Springer Nature

Año: 2022; p. 326 - 334

After being absorbed, most drugs will distribute unevenly across tissues and organs, sometimes to an extreme degree [1]. This is observed even after steady state (which indicates that it does not depend on purely kinetic factors, such as differential perfusion across different organs or tissues, or differences in the drug permeability across specific capillary beds). In fact, the main factors that may explain the heterogeneous distribution of a drug are the affinity of the drug for drug carriers and the affinity of the drug for tissue constituents. Drug molecules can reversibly interact with tissue constituents (e.g., proteins, lipids, nucleic acids, and others) in a nonspecific manner (here, ?nonspecific? is used in opposition to the specific, high-affinity interaction between the drug and its molecular target(s)). Such tissue constituents may be located intravascularly (as in the case of plasma proteins) or in the extravascular space. This entry will mainly focus on drug binding to extravascular tissues, as the interactions of the drug with plasma proteins are separately covered in the chapter on ?Drug Binding to Plasma Proteins?). Several tissues can thus assume a storage or depot function for a drug; the nonspecific drug binding to tissue constituents can then exert significant influence on essential pharmacokinetic parameters, such as clearance (CL), volume of distribution (Vd), and elimination or terminal half-life (t1/2). According to the free drug theory (see chapter on ?Free Drug Theory?), only the unbound drug molecules can engage in complexation with the drug target(s), and nonspecific tissue binding will directly influence on the dose, since a relatively high dose should be administered to compensate nonspecific distribution and attain effective unbound drug levels at the site of action, in pseudo-equilibrium with the bound concentrations across the different body compartments.