Distribution is the next phase, when the drug is transferred from the blood into tissues.5 To do so, it exits the vessels and enters the extravascular circulation, first into interstitial fluids, then into cells. Distribution may be subdivided into two successive phases. The first phase involves dilution of the absorbed dose in the whole blood as a free fraction, and binding to plasma proteins and circulating cells (e.g., erythrocytes). In the second phase, the drug distributes to organs. When the drug is injected intravenously as a bolus, a high local concentration occurs in blood before dilution, thus creating a high transitory gradient that reaches organs immediately downstream. This high gradient is sometimes required in order to obtain a quick and intense effect in well-irrigated organs (e.g., in the brain for general anesthetics). In many other cases, it may be dangerous as it promotes over dosage and possible toxic effects in heart and lungs.

In the blood, drugs are bound to plasma proteins according to the law of mass action (reversible equilibrium). The binding to a plasma protein may have two different meanings, either pharmacokinetic or pharmacodynamic. In the first case, the amount of bound drug and the characteristics of binding can alter the overall drug distribution. In the second, the drug is bound to its circulating receptor.

Many plasma proteins can bind drugs according to eqns [4] and [5]:

which gives:

where Ka is the association constant, CP is the protein concentration, Cb is the concentration of protein-bound drug, Cu is the free (unbound) drug concentration (with Cb + Cu = C, the total drug concentration in plasma), fu is the free fraction of drug in plasma (withfu = Cu/C), and 100(1 — fu) is the percentage of bound drug.

According to eqn [6],fu is not constant but increases when Cb increases. But when Cb is negligibly small compared to CP (Cb«CP) fu will be constant if the protein concentration is constant. Then:

Human serum albumin (HSA) and a1-acid glycoprotein (AGP) bind significant amounts of drugs as a consequence of their concentration and affinities. HSA concentration is high (ca. 630 mM), implying that Cb«CP is generally fulfilled, and HSA binding capacity for acidic drugs is generally high. In contrast, AGP concentrations are low (ca. 10 mM, except in some genetic or pathological states),6 and its affinity is mainly toward basic drugs, with the result that condition Cb«CP is not always fulfilled, binding is quickly saturated, and fu increases when drug concentration increases and binding percentage decreases.

Significant amounts of a drug may also be taken up by red cell membranes, or in the case of basic drugs in red cell cytosol at pH 7.20. Generally, uptake and binding to red cells are nonsaturable processes. When they are saturable, saturating concentrations will induce nonlinear kinetics.

Lipophilic drugs may also interact with lipoproteins,7 their dissolution in the lipid core of lipoproteins being roughly proportional to their lipid content (VLDL>LDL>HDL). Binding to the protein core has also been described but its pharmacokinetic significance is not yet established. The design of these various binding modes to plasma proteins has been described elsewhere.8 Other plasma proteins of pharmacokinetic interest are fibrinogen, a2-glycoprotein, and gamma globulins.

From the blood, drugs will distribute into organs at different rates corresponding to different membrane structures and different local blood flow rates. Schematically, drug distribution inside an organ is superimposable to the rate of blood flow. This observation explains why the blood cannot selectively distribute a drug into a given organ.

In every organ and every cell, a drug is partly free and partly bound to functional proteins, both forms being in reversible equilibrium. According to Brodie,9 it is assumed that at any time and in every tissue, an instantaneous equilibrium exists between blood and organ concentrations. This equilibrium is characterized by the same free drug

Organ 1

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