Phase nonspecific drugs

FIGURE 36-1 T Phases of the cell cycle. Examples of cell-cycle-specific drugs are listed next to the phase of the cycle they act on. Examples of cell-cycle-nonspecific drugs are listed below the figure. See text for more details. 

The isolation of both specific and nonspecific binding proteins on affinity matrices bearing bioactive compounds hinders the identification of drug cellular targets. While solid-phase elution or the competition methods are conventionally used to distinguish between specific and nonspecific receptor-ligand interactions, these approaches are often severely restricted by low ligand solubility and/or slow kinetic dissociation (8). This low solubility of these compounds are not uncommon, since the hydrophobic properties of these compounds are often vital for their bioactivity and/or membrane permeability. 

Fig. I. Endocytic pathways used by cells to internalize soluble macromolecules [25] fluid-phase pinocytosis (1), adsorptive pinocytosis (2), and receptor-mediated endocytosis (pinocytosis) (6). Each of these processes involves a formation of a sealed vesicle formed from the plasma membrane which encloses part of the extracellular medium. The internalization of a polymer-drug conjugate (P-D), and targeted polymer-drug conjugate ( => —P-D) is shown. Other abbreviations — = cell surface receptor/antigen 1 = clathrin molecule X = lysosomal enzyme. Fluid-phase pinocytosis (1) and adsorptive pinocytosis (2) are nonspecific processes which direct the macromolecule into the lysosomal compartment of the cell. Once P-D is internalized, whether by (1) or (2), the resulting endosome (3) is ultimately fused with a primary lysosome (4) forming a secondary lysosome (5). In the latter compartment P-D is in contact with several types of lysosomal enzymes. The membrane of (5) is impermeable to macromolecules. Consequently, the structure of P-D may be designed in such...

Concomitant medication should not be confused with rescue medications. The latter are nonspecific agents (or potentially effective drugs used in subtherapeutic doses) used so that patients can remain in the study for an adequate time, allowing for a valid comparison between the experimental agent and placebo (or standard drug). Often, rescue medications are used in the early phases and are decreased or eliminated before the critical evaluation at the end of the study. This enables more patients to complete the study (fewer dropouts), with the early impact of the rescue medication having at best only minimal effects on the final evaluations. 

Diethylstilbestrol is particularly difficult to quantitate below 1.0 ppb in bovine tissues, especially in liver, which is among the last tissues to contain diethystilbestrol after cattle are withdrawn from receiving tire drug (101, 102). Interferences from tissue matrix constitute a major problem that might be due to nonspecific interference of lipids and fatty compounds (103, 104). In addition, problems with false-positive results often appear in urine analysis unless a chromatographic step such as a solid-phase extraction cleanup (105, 106) is introduced. Simple sample preparation procedures such as those based on solvent extraction and liquid-liquid partitioning do not usually give satisfactory results (107, 108). 

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