Plasma compartment

After absorption, a chemical compound enters the circulation, which transfers it to all parts of the body. After this phase, the most important factor affecting the distribution is the passage of the compound through biological membranes. From the point of view of the distribution of a chemical compound, the organism can be divided into three different compartments (1) the plasma compartment (2) the intercellular compartment and (3) the intracellular compartment. In all these compartments, a chemical compound can be bound to biological macromolecules. The proportion of bound and unbound (free) chemical compound depends on the characteristics of both the chemical... 

Aqueous solubility is not usually considered a priori as a problem in the drug discovery of acidic compounds. More important issues are (i) the high serum albumin binding of stronger acids, (ii) the very low or nonexistent central nervous system penetration of stronger acids, (iii) the low volumes of distribution of acids limiting these mostly to plasma compartment targets, (iv) the possibility of formation of... 

Fig. 39.1. Two-compartment open model composed of a central (plasma) compartment and a target (skin) compartment. This model assumes that a dmg is delivered rapidly into plasma from which it is either exchanging with the target organ or eliminated by excretion or metabolism.

Figure 39.4a represents schematically the intravenous administration of a dose D into a central compartment from which the amount of drug Xp is eliminated with a transfer constant kp. (The subscript p refers to plasma, which is most often used as the central compartment and which exchanges a substance with all other compartments.) We assume that mixing with blood of the dose D, which is rapidly injected into a vein, is almost instantaneous. By taking blood samples at regular time intervals one can determine the time course of the plasma concentration Cp in the central compartment. This is also illustrated in Fig. 39.4b. The initial concentration Cp(0) at the time of injection can be determined by extrapolation (as will be indicated below). The elimination pool is a hypothetical compartment in which the excreted drug is collected. At any time the amount excreted must be equal to the initial dose D minus the content of the plasma compartment Xp, hence ...

This model is representative for the conditions described in the previous section, except for the mode of administration which can be oral, rectal or parenteral by means of injection into muscle, fat, under the skin, etc. (Fig. 39.7). In addition to the central plasma compartment, the model involves an absorption compartment to which the drug is rapidly delivered. This may be to the gut in the case of tablets, syrups and suppositories or into adipose, muscle or skin tissues in the case of injections. The transport from the absorption site to the central compartment is assumed to be one-way and governed by the transfer constant (Fig. 39.7a). The linear differential model for this problem can be defined in the following way ... 

Fig. 39.7. (a) Two-compartment catenary model for extravascular (oral or parenteral) administration of a single dose D which is completely absorbed. The transfer constant of absorption is (b) Time courses of the amount in the extravascular compartment Xa, the concentration in the plasma compartment Cp and the content in the elimination pool X. ... 

When j,p > k, the time course of the plasma concentration Cp is dominated by the rate of elimination which is the slower of the two. This is desirable when a drug must be delivered as rapidly as possible to the plasma compartment, for example in the relief of acute pain. At sufficiently large times following administration, the... 

If < fcpg, the time course of Cp is dominated by the slower rate of absorption. This is desirable when a drug is to be delivered over a prolonged period of time, for example in the relief of chronic pain. When a sufficiently large period of time has elapsed, the transient effect of elimination has decayed and the solution for the plasma compartment in eq. (39.16) becomes approximately ... 

In practice, the half-life time of the dmg in the plasma compartment is derived from the P-phase, and is therefore denoted as rf/2 ... 

The effect of incomplete absorption is that only a fraction of a single-dose D is made available to the central plasma compartment. The solution of the previous model needs, therefore, to be modified by replacing the term D by F D. Consequently the area under the curve AUCg under incomplete extravascular absorption will be smaller than the maximal AUC that results from complete absorption. The latter, as we have seen is equal to the AUC obtained from a single intravenous injection, which we denote by AUC,. These considerations can be summarized as follows ... 

In the previous discussion of the one- and two-compartment models we have loaded the system with a single-dose D at time zero, and subsequently we observed its transient response until a steady state was reached. It has been shown that an analysis of the response in the central plasma compartment allows to estimate the transfer constants of the system. Once the transfer constants have been established, it is possible to study the behaviour of the model with different types of input functions. The case when the input is delivered at a constant rate during a certain time interval is of special importance. It applies when a drug is delivered by continuous intravenous infusion. We assume that an amount Z) of a drug is delivered during the time of infusion x at a constant rate (Fig. 39.10). The first part of the mass balance differential equation for this one-compartment open system, for times t between 0 and x, is given by ... 

The transfer constant of elimination kp has already been shown to be related to the half-life time of the drug in the plasma compartment (eq. (39.9)) ... 

This model is an extension of the one-compartment model for intravenous injection (Section 39.1.1) which is now provided with a peripheral buffering compartment which exchanges with the central plasma compartment. Elimination occurs via the central compartment (Fig. 39.12). The model requires the estimation of the plasma volume of distribution and three transfer constants, namely for... 

In the catenary model of Fig. 39.14a we have a reservoir, absorption and plasma compartments and an elimination pool. The time-dependent contents in these compartments are labelled X, X, and X, respectively. Such a model can be transformed in the 5-domain in the form of a diagram in which each node represents a compartment, and where each connecting block contains the transfer function of the passage from one node to another. As shown in Fig. 39.14b, the... 

If X (0 and Xjit) are the input and output functions in the time domain (for example, the contents in the reservoir and in the plasma compartment), then XJj) is the convolution of Xj(r) with G(t), the inverse Laplace transform of the transfer function between input and output ... 

The general solution for the plasma compartment is now expressed as follows ... 

FIGURE 29-2. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma and brain compartments by an active transport mechanism. Levodopa is metabolized by dopa decarboxylase, monoamine oxidase, and catechol-O-methyltransferase. Carbidopa does not cross the blood-brain barrier. Large, neutral amino acids in food compete with levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport across the brain (plasma compartment to brain compartment). Food and anticholinergics delay gastric emptying resulting in levodopa degradation in the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes before or 60 minutes after meals. 

The increase in hematocrit on decreasing the plasma compartment has an effect of concentrating citrate and thus effectively increasing its concentration in plasma. The extra citrate present in the plasma compartment will complex with calcium added during PT and APTT measurements, thereby artifactually elevating both PT and APTT, because of insufficient calcium. This effect can be minimized by adjusting the citrate concentration in accordance with the hematocrit value by us-... 

Phenol red is rapidly cleared biphasically from the plasma compartment with an initial t of about 46 min. (Fig. 3) and a second phase with a t of 8 3 hrs. As early as 10 min. there are detectable levels or phenol red in the kidney. The concentration of drug in kidney peaked at 30 min. and decayed with a half-time of about 9 hrs. There also were detectable levels of phenol red within 10 min. in liver but the values were considerably below those of plasma and kidney. Hepatic levels took longer (ca. 2 hrs.) to peak than did those in kidney, and then decayed with a half-time of about 10 hrs. The glucuronide... 

The reason is that an acute inhibition of BSEP will lead to an elevated bile acid concentration both inside the hepatocytes as well as in the plasma compartment. But bile acids are, by themselves, signaling molecules that can upregulate their own... 

In the case of digoxin we can visualize what is happening. The site of action and binding site of digoxin is to tissue Na+K+ATPase. This enzyme is distributed very widely in tissues, and particularly in excitable tissue, which depends on it to restore sodium/potassium balance to resting levels after excitation. Digoxin preferentially distributes therefore to these tissues, and a disproportionately small component is left in the plasma compartment from which we sample. 

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