Physical volume of an organism

This concept is related to multi-compartmentalization. Any drugs within an organism will act as a solute and the organism's tissues will act as solvents. The differing specificities of different tissues will give rise to different concentrations of the drug within each group. Therefore, the chemical characteristics of a drug will determine its distribution within an organism. For example, a liposoluble drug will tend to accumulate in body fat and water-soluble drugs will tend to accumulate in extracellular fluids. The volume of distribution (V_D) of a drug is a property that quantifies the extent of its distribution. It can be defined as the theoretical volume that a drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. It can be determined from the following formula: ${\displaystyle Vd={\frac {Ab}{Cp}}\,}$ Where: ${\displaystyle Ab}$ is total amount of the drug in the body and ${\displaystyle Cp}$ is the drug's plasma concentration.

As the value for ${\displaystyle Ab}$ is equivalent to the dose of the drug that has been administered the formula shows us that there is an inversely proportional relationship between ${\displaystyle Vd}$ and ${\displaystyle Cp}$. That is, that the greater ${\displaystyle Cp}$ is the lower ${\displaystyle Vd}$ will be and vice versa. It therefore follows that the factors that increase ${\displaystyle Cp}$ will decrease ${\displaystyle Vd}$. This gives an indication of the importance of knowledge relating to the drug's plasma concentration and the factors that modify it.

If this formula is applied to the concepts relating to bioavailability, we can calculate the amount of drug to administer in order to obtain a required concentration of the drug in the organism ('loading dose):

${\displaystyle Dc={\frac {Vd.Cp}{Da.B}}}$

This concept is of clinical interest as it is sometimes necessary to reach a certain concentration of a drug that is known to be optimal in order for it to have the required effects on the organism (as occurs if a patient is to be scanned).

Removal rate

A drug's removal rate will be determined by the proportion of the drug that is removed from circulation by each organ once the drug has been delivered to the organ by the circulating blood supply.^[1] This new concept builds on earlier ideas and it depends on a number of distinct factors:

• The drugs characteristics, including its pKa.
• Redistribution through an organism's tissues: Some drugs are distributed rapidly in some tissues until they reach equilibrium with the plasma concentration. However, other tissues with a slower rate of distribution will continue to absorb the drug from the plasma over a longer period. This will mean that the drug concentration in the first tissue will be greater than the plasma concentration and the drug will move from the tissue back into the plasma. This phenomenon will continue until the drug has reached equilibrium over the whole organism. The most sensitive tissue will therefore experience two different drug concentrations: an initial higher concentration and a later lower concentration as a consequence of tissue redistribution.
• Concentration differential between tissues.
• Exchange surface.
• Presence of natural barriers. These are obstacles to a drug's diffusion similar to those encountered during its absorption. The most interesting are:
  • Capillary bed permeability, which varies between tissues.
  • Blood-brain barrier: this is located between the blood plasma in the cerebral blood vessels and the brain's extracellular space. The presence of this barrier makes it hard for a drug to reach the brain.
  • Placental barrier: this prevents high concentrations of a potentially toxic drug from reaching the foetus.

Plasma protein binding

Some drugs have the capacity to bind with certain types of proteins that are carried in blood plasma. This is important as only drugs that are present in the plasma in their free form can be transported to the tissues. Drugs that are bound to plasma proteins therefore act as a reservoir of the drug within the organism and this binding reduces the drug's final concentration in the tissues. The binding between a drug and plasma protein is rarely specific and is usually labile and reversible. The binding generally involves ionic bonds, hydrogen bonds, Van der Waals forces and, less often, covalent bonds. This means that the bond between a drug and a protein can be broken and the drug can be replaced by another substance (or another drug) and that, regardless of this, the protein binding is subject to saturation. An equilibrium also exists between the free drug in the blood plasma and that bound to proteins, meaning that the proportion of the drug bound to plasma proteins will be stable, independent of its total concentration in the plasma.

In vitro studies carried out under optimum conditions have shown that the equilibrium between a drug's plasmatic concentration and its tissue concentration is only significantly altered at binding rates to plasma proteins of greater than 90%. Above these levels the drug is "sequestered", which decreases its presence in tissues by up to 50%. This is important when considering pharmacological interactions: the tissue concentration of a drug with a plasma protein binding rate of less than 90% is not going to significantly increase if that drug is displaced from its union with a protein by another substance. On the other hand, at binding rates of greater than 95% small changes can cause important modifications in a drug's tissue concentration. This will, in turn, increase the risk of the drug having a toxic effect on tissues.

Perhaps the most important plasma proteins are the albumins as they are present in relatively high concentrations and they readily bind to other substances. Other important proteins include the glycoproteins, the lipoproteins and to a lesser degree the globulins.

It is therefore easy to see that clinical conditions that modify the levels of plasma proteins (for example, hypoalbuminemias brought on by renal dysfunction) may affect the effect and toxicity of a drug that has a binding rate with plasma proteins of above 90%.