Passage of drug across biological membrane

Passage of drug across biological membrane

Passive diffusion

Passive diffusion is a random movement of drug molecules from an area of higher concentration to an area of lower concentration. When a drug is injected into the body, it passively diffuses from the injection site to areas of lower concentration, eventually reaching a blood capillary and entering the systemic circulation. In this process no cellular energy is expended and no transport carrier protein is involved. Hence the term passive diffusion is used.

Many drugs pass through the biological membranes such as cell membranes by passive diffusion. For a drug to passively diffuse from one side to another, the drug must dissolve in the membrane that is composed of phospholipids, and diffuse down the concentration gradient.

Passive diffusion continues until enough molecules have passed from an area of higher concentration to an area of lower concentration till equilibrium is attained on either side of the membrane. Drug molecules continue to move, however, such that an equal number move into and out of both the areas.

Passive diffusion is the most important mechanism for majority of drugs. Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the membrane. The rate of transport being proportional to lipid: water partition coefficient of the drug.

Passive diffusion is mostly dependent upon

1. Concentration gradient (greater is the difference in the concentration of the drug on the two sides of the membrane, faster is its diffusion)
2. Drug molecular size (smaller molecules move more rapidly than bigger molecules)
3. Lipophilic nature of the molecule (higher the lipid solubility higher is the diffusion)
4. Temperature (lower the temperature, slower the diffusion)
5. Thickness of the membrane (the thicker the membrane the slower the diffusion)

Carrier mediated transport

• In Carrier mediated transport, the drug combines with a carrier present in the membrane and the complex then translocates from one side of the membrane to the other.
• The carriers for polar molecules appear to form a hydrophobic coating over the hydrophyllic groups and thus facilitate passage through the membranes. Substances permitting transit of ions across membranes are called ionophores.
• Carrier transport is specific, saturable and competitively inhibited by analogues that utilise the same carrier. Intestinal absorption sometimes depends on carriermediated transport. 
• Examples of carrier mediated transport are: 
• levodopa is taken up by a carrier that normally transports phenylalanine;
• flurouracil is transported by the system that carries natural pyrimidines;
• iron is absorbed via a specific carrier on the surface of the mucosal cells in the jejunum and
• calcium is absorbed by means of a vitamin D dependent carrier system.
• This carrier mediated transport is of two types, namely
  • facilitated diffusion and
  • active transport

Facilitated diffusion

Facilitated diffusion is a transport mechanism across biological membranes that involve a special “carrier molecule” in the membrane which facilitates the movement of certain molecules across the membrane.

As in passive diffusion, facilitated diffusion involves no energy to move the drug molecules and the direction of the drug movement is determined by the concentration gradient.

In addition, once the equilibrium is attained, the number of drug molecules crossing the membrane in either direction remains the same.

This process proceeds more rapidly than simple diffusion and even translocates non-diffusible substrates, but along their concentration gradient.

However, the transporter may become saturated and other compounds may compete or inhibit the transport.

• Examples of facilitated diffusion are-
  1. Vitamin B12 absorbed from the gut .
  2. Transport of sugars and amino acids across membranes.

Active transport

Like facilitated diffusion, active transport also involves a specialized carrier molecule. However, in active transport a drug molecule is taken up by a specialized carrier molecule in the membrane and the cell expends energy to move the drug molecules across or to “reset” the carrier molecule for the next transport movement.

Unlike diffusion in which the direction of net drug movement is determined by the concentration gradient, active transport can move drug molecules against the concentration gradient (from areas of lower concentration to areas of higher concentration).

Glucose entry within cell is facilitated diffusion while passage across gastric mucosa and excretion by proximal renal tubular cells is active transport.

Drugs related to normal metabolites are actively absorbed from the gut by aromatic amino acid transport processes.

Drugs actively transported may potentially reach very high  concentrations within cells that they exert a toxic effect eg. aminoglycoside antibiotics.

When the energy production of the cell is disrupted (such as toxicities), active transport of drug molecules across biological membranes may be prevented.

Nonspecific active transport of drugs and their metabolites occurs in renal tubules and hepatic sinusoids separately for organic acids and organic bases. Certain drugs have been found to be actively transported into the brain and choroid plexus also.

Examples for active transport are levodopa crossing the blood brain barrier, secretion some drugs into the bile and secretion of many organic acids and bases by renal tubular cells.

Pinocytosis and phagocytosis

Pinocytosis (Cell drinking) and phagocytosis (Cell eating). Drug molecules may enter a cell by being physically engulfed by the cell. In both pinocytosis and phagocytosis, a portion of the cellular membrane surrounds the drug molecule and takes it within the cell.

In these processes transport across the cell membrane is facilitated by formation of vesicles. This is an active process and requires the cell to expend energy. If the engulfed particle is not susceptible to enzyme degradation, it will persist like particles of talc or droplets of liquid paraffin.

Pincytosis and phagocytosis are especially important for movement of large drug molecules such as complex proteins or antibodies that would otherwise be unable to enter a cell or pass intact through a membrane barrier. The absorption of immunoglobulins through the gut mucosa of young calves depends on phagocytosis.

Filtration

Filtration is the passage of drugs through aqueous pores in the membrane or through paracellular spaces. This can be accelerated if hydrodynamic flow of the solvent is occurring under the hydrostatic or osmotic pressure gradient.

Lipid insoluble drugs cross biological membranes by filtration if their molecular size is smaller than the diameter of the pores. Majority of the cells have very small pores and drugs with higher molecular weight will not be able to penetrate. However capillaries (except those in brains) have large pores and most drugs can filter through these pores.

Passage of drugs across capillaries is dependent on the rate of blood flow through them rather than on lipid solubility of the drug or pH of the medium.

Filtration seems to play almost a minor role in drug transfer within the body except for glomerular filtration, removal of drugs from CSF and passage of drugs across hepatic sinusoidal membrane.