Four factors govern the extent to which drugs move out of the blood into tissues:
- Ability to undergo passive diffusion
- Binding to macromolecules
- Ion trapping
Ability to undergo passive diffusion: We have already seen that most drugs rely on passive diffusion in order to cross biological membranes and hence undergo absorption into the blood. We also saw that the ability to undergo this process depended primarily upon adequate lipid solubility.
Similar logic applies to distribution from blood to tissues. Very water soluble molecules will undergo passive diffusion inefficiently and distribute from the blood into tissues either slowly (e.g. digoxin) or hardly at all (e.g. gentamicin).
Binding to macromolecules
Drugs cannot undergo passive diffusion while bound to a macromolecule such as a protein or DNA. Take the example of blood albumin, which binds a wide range of drugs. The protein molecule is far too water soluble to undergo passive diffusion. Albumin is much larger than most drug molecules and the physical chemistry of a drug-protein complex is dominated by the protein moiety — it is also water soluble and incapable of undergoing passive diffusion. Consequently drugs that are bound to macromolecules are effectively trapped on one side of a biological membrane, unable to distribute to the other side. Below Figure shows drug movement between blood and tissues and the effect of binding to a macromolecule (such as albumin) in blood.
Free (unbound) drug molecules are assumed to be lipid soluble and freely able to move in either direction across the lipid membrane. Drug bound to a blood protein is trapped in the blood. At equilibrium, concentrations of free drug will be equal on both sides of the membrane. However, total drug concentration will be higher in the blood because of the additional protein bound material.
We saw how P-glycoproteins in the gut can actively pump drugs across membranes and hence inhibit drug absorption. P-glyoproteins are also present in other parts of the body and have an effect upon drug distribution between blood and tissues.
P-glycoproteins seem to have evolved as a mechanism to protect the body from toxic molecules that may be ingested. The central nervous system (CNS) is particularly sensitive to poisoning and one line of defence consists of P-glycoproteins at the blood brain barrier, which prevent the entry of toxins (and certain drugs) into the CNS.
Ion trapping arises when an ionisable drug encounters a pH gradient. An example is shown in below Figure.
The example in above Figure, assumes that a basic drug contains an ionisable nitrogen atom. The stomach contents are strongly acidic, while blood and tissues are approximately neutral. In its non-ionized form the drug is lipid soluble and able to cross membranes by passive diffusion. However, once ionized it is much more polar and unable to cross.
A sequence of events arises:
– The highly acidic environment within the stomach, causes an extensive shift in the equilibrium between ionized and non-ionized drug towards ionization (Hence the dominant arrow in the appropriate direction)
– The process described above, reduces the concentration of non-ionized drug in the stomach and creates a disequilibrium, with a lower concentration of non-ionized material in the stomach than in the blood. Consequently, non-ionized drug moves into the stomach contents.
– This physical movement depletes the concentration of non-ionized drug in the blood, causing a disequilibrium between ionized and non-ionized drug. This is resolved by re-equilibration – the conversion of ionized into non-ionized drug within the blood.