Drug distribution from blood

Drug in blood and equilibrium between compartments

At equilibrium, a given plasma concentration of a drug corresponds to a given tissue concentration, i.e. blood mirrors what occurs in the whole body, although the concentrations in various tissues are generally different.

The measurement of the plasma concentration allows a monitoring of the treatments for avoiding toxic or ineffective concentrations, provided that sample of blood for the determination is performed at one well defined time after the administration of the drug to obtain comparable results.

Only the free fraction of the drug, i.e. the diffusible fraction is responsible for the equilibrium plasma/tissue concentrations. However, the ratio bound on free form is generally constant and the measurement of the total concentration of the drug is sufficient for therapeutic monitoring.

The desired plasma concentrations of a certain number of drugs, lower than their toxic and higher than their minimum effective concentration, called therapeutic windows, are known.

Binding to proteins

In blood drugs can bind reversibly to proteins. The concentration of proteins in plasma is normally 60 to 70 g/L. Certain plasma proteins play a part in the binding of the drugs:

  • Albumin whose molecular weight is 68 000, is made of a polypeptide chain with many disulfide bonds. Its half-life is about three weeks. It binds especially acid drugs such as nonsteroidal antiinflammatory drugs, lipid-lowering drugs and endogenous molecules like fatty acids, thyroxine and estradiol. In addition to its role in the transport of endogenous compounds and drugs, it ensures the intravascular oncotic pressure and opposes extravascular water escape. In patients with hypo-albuminemia, lower than 20 g/L, it is necessary to correct the deficiency by administration of albumin which, at present, is obtained from human blood.
  • Alpha-1 acid glycoprotein, also called orosomucoid, very rich in carbohydrates and sialic acid which gives it an acid property. It binds especially basic molecules like lidocaine, prazosin.
  • Lipoproteins which bind certain drugs like chlorpromazine and imipramine.
  • Immunoglobulins such as IgG whose plasma concentration is around 15 g per liter.

Blood cells, in particular erythrocytes when they bind or take up certain drugs, play a role of temporary reservoir.

Binding of drugs to proteins depends on several factors:

  1. The affinity of the drug for the binding sites on proteins. The binding can go from 0 to nearly 100%. The binding of anti-inflammatory drugs like indomethacin, certain antidepressants like imipramine, is higher than 95%. The binding of phenobarbital, of theophylline is about 50%. The binding of isoniazid, of acetaminophen is negligible.
  2. The quantity of proteins which can vary according to the physiological or pathological state. For example, immobilization, bed rest, traumatisms, burns, pregnancy, cirrhoses decrease it whereas nephrotic syndromes, anxiety increase it.
  3. Concentration of the drug: if a drug is present in sufficient concentration to saturate its binding sites, all new intake occurs as if the binding did not exist.
  4. The competition between a drug and another molecule:
    1. competition between two drugs for a same site, one drug can displace the other: salicylic acid displaces indomethacin, clofibrate antivitamins K. The freed drug can act and cause effects but it is also quickly is metabolized and eliminated.
    2. competition between a drug and an endogenous product: fatty acids and bilirubin which are also bound to albumin enter in competition with acid drugs.

The essential feature of the binding of drugs to proteins is to be reversible according to the following reaction where D indicates the drug, P, the protein and DP the drug bound to protein.

[Drug + Protein] <=> [Drug - Protein]

  • There is an equilibrium between the free form and the bound form: when the concentration of D increases, the reaction is carried out in direction 1 and when it decreases, in direction 2.
  • Only the free form [D] is active. It diffuses through membranes and the equilibrium between compartments is established according to its concentration. It is also the form which is eliminated and metabolized.
  • The bound form [DP] can be regarded as a buffer, a form of store which does not cross the membranes.
  • The binding of a drug to proteins reduces its dialysance and consequently the efficacy of dialysis used as mean of detoxification during poisoning.
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