Equilibrium Dialysis

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Equilibrium dialysis is based on the establishment of an equilibrium state between plasma containing a drug and a buffer after a period of incubation, usually longer than 2 hr, at a fixed temperature (e.g., 37°C). The equilibrium dialysis chambers for plasma containing a drug and a buffer free of drug are separated by a semipermeable membrane, which allows only low-molecular-weight ligands, such as drug molecules, to transport between the two chambers (Fig. 7.2). Sodium or potassium phosphate buffers at pH 7.4 are the ones most commonly used, although for some compounds others are required owing to the formation of insoluble salts or interactions with drug binding sites in protein molecules.

As illustrated in Fig. 7.2, water molecules from the buffer side are continuously moving into the plasma side during incubation because of the difference in osmotic pressure between the plasma and the buffer and/or the Donnan ion effect. This phenomenon is called the "volume shift," i.e., an increase in plasma volume and a decrease in buffer volume compared to their initial values. The ratio of unbound and total drug concentrations in plasma (fu) can be estimated after equilibrium dialysis using the following equation with a correction factor for the volume shift, which is usually about 15-20%:

(Cpe - Cbe)-(Vpe/Vpb) + Cbe Cpe and Cbe are the concentrations of the drug in the plasma and buffer sides of the

Equilibrium Dialysis

Figure 7.2. Schematic description of the equilibrium dialysis process between drug molecules not (•) bound to proteins (O) in plasma and a buffer with no drug molecules via a semipermeable membrane. There is a volume shift from the buffer side to the plasma side, while reaching an equilibrium of free drug molecules between the two sides owing to the higher osmotic pressure of the plasma containing the drug.

Figure 7.2. Schematic description of the equilibrium dialysis process between drug molecules not (•) bound to proteins (O) in plasma and a buffer with no drug molecules via a semipermeable membrane. There is a volume shift from the buffer side to the plasma side, while reaching an equilibrium of free drug molecules between the two sides owing to the higher osmotic pressure of the plasma containing the drug.

equilibrium chambers at equilibrium after incubation, respectively, and Vpb and Vpe are the original volume of the plasma before incubation and the volume of the plasma at equilibrium after incubation, respectively. It should be stressed that maintenance of physiological temperature and pH during the experiment is important for accurate assessment of protein binding of drugs (Boudinot and Jusko, 1980; McNamara and Bogardus, 1982; Tozer et al., 1983).

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