Effects of Organ Size Blood Flow and Partition Coefficient on Distribution

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A particular organ in the body may act as a site of distribution or as a site of both distribution and elimination. The relative importance of the various organs as storage or aExcerpted from Oie and Benet, Modern Pharmaceutics, 4th Edition.

Organ Blood Distribution

Figure 1 Process of drug absorption and distribution following administration of a single dose. The drug reaches the desired site of action either directly or via the general circulation. The drug may also reach other tissue sites or may be eliminated by physiologic clearance mechanisms. Source: Modified from Ref. 1.

Figure 1 Process of drug absorption and distribution following administration of a single dose. The drug reaches the desired site of action either directly or via the general circulation. The drug may also reach other tissue sites or may be eliminated by physiologic clearance mechanisms. Source: Modified from Ref. 1.

elimination sites depends on how fast the drug gets to each organ and how much space or volume is available to hold the drug. Table 1 presents a compilation of the volumes and blood flows of the different regions of the human body for an average adult male, as compiled by Dedrick and Bischoff (2) by using the mean estimates of Mapleson (3).

The various regions of the body are listed in decreasing order relative to blood flow per unit volume of tissue (adrenals highest and bone cortex lowest). This value essentially describes how fast a drug can be delivered to a body region per unit volume of tissue and reflects the relative rates at which tissues may be expected to come to equilibrium with the blood. How much drug can be stored or distributed into a tissue will depend on the size of the tissue (volume) and the ability of the drug to concentrate in the tissue (i.e., the partition coefficient between the organ and blood, KO/B). For example, the blood flow per unit volume of thyroid gland (Table 1) is one of the highest in the body, whereas the gland itself is quite small. Thus, if partition of the drug between the thyroid and blood were approximately 1, we would expect to see that the drug in the tissue would rapidly come into equilibrium with that in the blood but that a relatively small total amount of drug would actually be present in the thyroid. In comparison, for certain drugs containing iodine moieties, KO/B for the thyroid is very large, and a significant amount of drug will distribute into this small gland relatively rapidly. In addition, Table 1 lists the volume of blood contained within each tissue and is believed to be in equilibrium with the tissue. Thus, the volume of the thyroid in Table 1 is considered to be 20 mL of tissue and 49 mL of blood. Note that total volume of all tissues in column 3 is 70 L, including the 5.4 L of blood volume. This blood volume can be further categorized into 1.4 L of arterial blood (listed in the last column as being in equilibrium with the air in the lungs) and 4 L of venous blood (in equilibrium with tissues A through O).

When discussing drug distribution, it is often convenient to combine various tissue regions into general categories. For example, following an IV bolus injection, the heart,

Table 1 Volumes and Blood Supplies of Different Body Regions for a Standard Mana

Volume of blood in equilibrium

Reference Volume Blood flow Blood flow with tissue Tissue letters (L) (mL/min) (mL/100 mL) (mL)

Adrenals A 0.02

Kidneys B 0.3

Thyroid C 0.02

Gray matter D 0.75

Heart E 0.3

Other small glands and F 0.16 organs

Liver plus portal system G 3.9

White matter H 0.75

Red marrow I 1.4

Muscle J 30 Skin

Nutritive K 3

Shunt L

Nonfat subcutaneous M 4.8

Fatty marrow N 2.2

Fat O 10.0

Bone cortex P 6.4

Arterial blood Q 1.4

Venous blood R 4.0

Lung parenchymal tissue S 0.6

Tidal Volume

Total 70.0d

100 500 62

1240 410 765

80 400 49

600 80 371

240 80 148

80 50 50

1580 41 979

160 21 100

120 9 74

300/600/1500 1/2/5 185/370/925

30/60/150

1620/1290/300 54/43/10

200 2.0 123

1400b

999/795/185c

6480 5400

'Standard man = 70-kg body weight, 1.83-m2 surface area, 30-39 years old. bArterial blood. cSkin-shunt venous blood. dExcluding the air in the lung.

brain, liver, and kidneys achieve the highest and earliest drug concentrations, with equilibrium between these tissues and blood being rapidly achieved. Thus, Dedrick and Bischoff (2) combined these tissues and other well-perfused regions (see A through H in Table 1) into a well-perfused compartment that they designate as the viscera. Similarly, regions I, J, K, and M are combined into a "lean tissue" compartment, whereas poorly perfused regions N and O are designated as the adipose compartment. Blood flows and volumes for these compartments can be calculated by summing the appropriate terms in Table 1.

Using a similar perfusion model containing these three lumped compartments and a blood compartment, Bischoff and Dedrick (4) were able to describe thiopental concentrations in various tissues, as shown in Figure 2. Concentrations in the dog liver, representative of the visceral tissues, are already at a maximum by the time the first sample is taken, since very rapid equilibrium is achieved between these tissues and the blood. Drug uptake into the less well-perfused skeletal muscle, representative of the lean tissue, is slower, with a peak concentration occurring at about 20 minutes with an

Partition Coefficient Drugs

Figure 2 Thiopental concentration in various tissues following 25 mg/kg IV bolus doses. Solid symbols indicate data in dogs; the open circles represent data from humans. Lines correspond to predicted values in various tissues using a perfusion model containing compartments corresponding to the blood, viscera, lean, and adipose tissues. Source: From Refs. 1 and 4.

Figure 2 Thiopental concentration in various tissues following 25 mg/kg IV bolus doses. Solid symbols indicate data in dogs; the open circles represent data from humans. Lines correspond to predicted values in various tissues using a perfusion model containing compartments corresponding to the blood, viscera, lean, and adipose tissues. Source: From Refs. 1 and 4.

apparent distribution equilibrium occurring between one and two hours. Uptake into the poorly perfused adipose tissue is even slower. In fact, peak levels in this tissue had not been reached by the time the last samples were taken.

Since the site of action for the barbiturates is the brain, we might expect the pharmacologic activity to correspond to the time course of thiopental concentrations in the viscera, which, in turn, would be approximated by blood levels, since a rapid equilibrium is attained between the viscera and the blood. Although the pharmacologic action of thiopental may terminate quickly (within an hour) owing to decreased blood and brain concentrations, traces of the drug may be found in the urine for prolonged periods (days) owing to accumulation in the fatty tissues. At 3/ hours, most of the lipid-soluble thiopental left in the body is in the fat, and at later times, this percentage may even increase before distribution equilibrium is reached. At these later times, the removal rate of the barbiturate from the body will be controlled by the slow movement of drug out of the fatty tissue as a result of the high partition into the fat and the low blood flow to this region.

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  • kenzie
    What is meant by partition coefficient between organ and blood?
    3 years ago
  • annett
    How size of the orggan effect drurug disdistribution?
    3 years ago
  • oran
    How size of organ afect drug distibution?
    2 years ago

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