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Tissue distribution of drugs

The drug diffuses from the plasma in the whole body. The distribution depends on the drug and tissues.

  • Drug: its plasma concentration in free form and of its physicochemical characteristics, in particular of its liposolubility.
  • Tissue or organ: existence of specific membranes, importance of the irrigation (blood flow rate) and tissue composition giving more or less affinity for a particular compound. Thus, the cerebral tissue rich in lipids has a great affinity for liposoluble molecules.

These features explain why the drug is distributed in a nonhomogeneous manner in the different organs. For example, chloroquine concentration is 700 times higher in the liver than in plasma.

Transfer into the central nervous system and the cerebrospinal fluid

The central nervous system weighs 2% of the weight of the body, receives 16% of the cardiac output (brain: 0,5 ml blood/g/minute, muscle at rest: 0,05 ml blood/g/minute). The white compound is less better irrigated than the gray one.

In spite of this excellent irrigation, a certain number of compounds do not penetrate into the brain. The membrane of the cerebral capillaries is doubled by a tissue of glial support, the astrocytes, thus creating a double barrier - capillary endothelium and glial membrane - not very permeable to the non-liposoluble molecules. Alterations of the barrier, in case of anoxia in particular, are likely to deteriorate its permeability.

Liposoluble molecules and gases, for example inhalational anesthetics, penetrate easily in the brain by passive diffusion.

The polar molecules (ionized) do not penetrate or little by passive diffusion. Atropine, for example, crosses, but its positively charged quaternary form does not penetrate. Penicillin does not penetrate.

Various polar compounds, ions, sugars, amino acids and even certain peptides like insulin, cross the blood-brain barrier by using endogenous carriers. It is a secondary active transport. One can quote some of these carriers:

  • Glut-1, glucose carrier non-dependant on insulin, which can also transfer some glycopeptides
  • LNA system (large neutral amino acids) which allows the influx of certain amino acids and drugs having a similar structure, such as L-dopa, melphalan, gabapentin, baclofen
  • peptide carriers
  • receptors, such as those of transferrin which are internalized by endocytosis.

In addition, certain compounds such as bradykinin distend intercellular tight junctions and facilitate the transfer of various compounds through the blood-brain barrier.

The transfer of a drug from brain into blood and peripheral organs is called redistribution. A drug such as thiopental which is very liposoluble, after intravenous administration penetrates very quickly into the brain, rich in lipids and well irrigated, where its concentration is quickly maximum. In a second time, the other fat tissues less irrigated than the brain accumulate thiopental, inducing a displacement of the product from the brain towards blood and peripheral fat tissues. This redistribution explains why thiopental acts very quickly and that its duration of action is short.

The cerebrospinal fluid secreted by the choroid plexus has a volume of approximately 150 to 200 ml. Its rate of renewal is approximately 0.5 ml/minute. Normally, it does not contain proteins. The concentration of a drug which diffuses passively in the cerebrospinal fluid is approximately equal to the concentration of its free form in plasma.

Modifications of tissue distribution

The distribution of a drug in certain parts of the body or of a tissue can be modified under pathological conditions, in particular in patients with circulatory disorders.

The distribution can also be voluntarily modified by electroporation. The electroporation is a technique which consists in subjecting tissues to impulses of electric field which increase the permeability of the plasma membrane by opening pores. It is called electrochemotherapy when it is used in cancerology.

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  Last update : August 19, 2006  
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