3.2 Absorption of Drugs

3.2.1. Routes of Administration

There are many different routes by which a drug can enter the body, and the route has a large impact on how fast the drug is taken up and how much of it arrives at its destination in an active form. Table 3.2.1. outlines some of the routes of administration with an indication of some of the advantages and disadvantages of each.

Table 3.2.1. Routes of Drug Administration

Route

Advantage

Disadvantage

Oral

Convenient
Efficient Absorption
(huge surface area)
Drug degradation
Requires lipid permeation
Gastric irritation
Frist pass effect

Inhalation

Large surface area
Access nasal or lungs
Rapid delivery to blood
Requires special properties
(vaporized, atomized)
Nasal proteases
Irritation

Topical

Convenient
Rapid
Localized

Only local

Transdermal

Prolonged Release

Lipid permeation
Initial time lag
Dermal enzymes

Buccal

Self administered
No first pass effect

Drug must be lipid soluble and potent

Intravenous

Direct
Rapid
Programmable
Hazardous
Requires professional

Intramuscular

Rapid for aqueous
Slow depot for oil

Pain, inflamation at delivery site

Others: Intrarteria,
Intrathecal,
Intraperitoneal

The most common route is the oral route. This route is convenient and very efficient, with a huge surface area and compartments of different pH which can accommodate drugs with different solubilities. Drawbacks include the fact that many compounds, proteins for example, and broken down by the GI enzymes and harsh pH conditions, and the fact that the drug has to have considerable lipid solubility to pass through the fatty cell membranes of the gut wall to reach the blood supply. Another important phenomenon, alluded to earlier, called the first pass effect reduces the availability of many drugs. It results form the arrangement of the blood vessels that permeate and drain the GI tract, (with the exception of the lower rectum). Most vessels from the GI drain into the portal vein, which goes to the liver. The liver is the waste management system of the body, breaking down waste and detoxifying compounds. If a drug goes first to the liver it is likely that a large degree of degradation will take place.

One route that has become widely studied recently is the transdermal route. Many skin patches have come onto the market, including ones containing the anti angina drug nitroglycerine, patches for hormone replacement therapy, and ones for motion sickness containing scopolamine, which have even found their way on board the space shuttle. The main problem here is that the drug has to be able to permeate the fatty layers of the skin. Research is ongoing to find ways of encouraging large molecular weight proteins through the skin, opening up the pores in the skin either by chemicals, know as enhancers, or by physical means such as applying an electric field (iontophoresis) or ultrasound energy (sonophoresis).

The traditional route for insulin is intramuscular. This involves injection directly into the muscle of the leg, arm or abdomen. The uptake can be quite rapid if the insulin is in an aqueous solution, but if it is in an oily solution diffusion away from the site of injection is inhibited, and the effect is for the oil suspension to act as a slow release depot. Figures 3.2.1 and 3.2.2 give some idea of how the muscle into which the injection takes place can affect the uptake, as well as the presence or absence of exercise. Figure 3.2.1 is a representation of results from Kiovisto in the English Journal of Medicine and shows the change in plasma glucose levels after insulin is injected into either the leg, arm or abdomen, during one hour of exercise and for a subsequent 6 hours. Since the lowering of blood glucose levels is directly related to the amount of insulin absorbed, it can be seen that significantly more insulin is taken up from the leg muscle, which presumably has a much greater blood flow during exercise, than from the other two sites

Figure 3.2.2. shows that the amount of radio labeled insulin that is taken up following subcutaneous insulin injection was far greater with exercise, presumably again a function of greater blood flow. The use of a drug which has been changed so that it contains an atom which is radioactive, a so-called radio-labeled compound, is frequently used in drug delivery research. It is very easy for the researcher to follow where the drug goes by measuring the amount of radioactivity that is present. When the experiment is performed in volunteers, the levels of radiation are kept very low, so as not to harm the volunteer.

Figure 3.2.1. Influence of injection site on the plasma glucose response to insulin during exercise (leg) and in the absence of exercise (arm and abdomen). (After Kiovisto et al. 1978)

Figure 3.2.2. Effect of exercise on plasma levels of 3H-insulin following subcutaneous injection. After Berger et al. 1979.

3.2.2. Factors that affect Drug Absorption

Many factors can effect the rate and extent of drug absorption. A very important factor is the solubility of the drug. If the drug is soluble in an aqueous solution it will be absorbed by the surrounding tissue, more rapidly than a drug that is dissolved in an oily solution. However, in the GI tract, the situation is complicated by the need for the drug to have some lipid solubility in order to pass through the cell membranes of the intestine wall and blood vessels and into the blood. So the drug needs to be water soluble and fat soluble at the same time for optimal absorption. In addition a drug that can be ionized will pass through a membrane better in the un-ionized form. This means that weak acids will cross better at a pH lower than the pKa, and weak bases will cross better at pH above their pKa. The pKa of a substance is defined as the negative logarithm of the dissociation constant, and is equal to the pH at which the concentrations of the acid and base form are equal. However, the ionized form of a drug is more soluble, and a drug must be in solution to be absorbed.

Also the rate at which the drug dissolves at a particular site will have a profound effect on the absorption rate. This can be strongly influenced by the local conditions. Some drugs, for example, and not soluble in the acid of the stomach, but are soluble in the alkaline conditions of the GI tract.

The GI tract is also a good example of how stability of a drug can effect its absorption. Many drugs that are of interests today, such as proteins, are not stable in either the acid environment of the stomach, or the alkaline environment of the intestine, which is rich in protein degrading enzymes .

Not only solubility and stability but also residence time at a site can be a factor. Many researchers have investigated the use of substances, called bioadhesives, which will hold a drug at a particular site. Drug washout is particularly prevalent in the eye. The tears of the eye wash over 95% of an applied aqueous dose of drug away into the nasolachrymal duct. Any vehicle that can prevent this from happening will greatly increase the absorption of the drug in the eye. Another example of drug loss is the rapidity of stomach emptying. If you want absorption of your drug from the stomach it is best to take it after a heavy, fatty meal, when the chances of the stomach emptying are diminished. The best way to get it rapidly into the intestine is to take it on an empty stomach with a lot of fluid, since fluid tends to increase stomach contractions.

Drug concentration is an interesting, and contradictory factor in drug absorption. Often high concentrations lead to more rapid absorption, as would be expected since the driving force is greater. However, sometimes in GI absorption this is not the case. Often absorption increases when the drug is either taken as a pill with a large volume of water, or as a dilute solution. The factors that are now becoming important are a more rapid stomach emptying as mentioned above, an increase in surface area contacted by the large volume of the solution, and in the case of a pill, a larger volume of water in which to dissolve more rapidly. This is only true for the GI or enteral route. Any route other than by mouth is known as parenteral administration.

In addition to the concentration of drug, the blood flow at the absorption site can greatly influence absorption, which will be increased with increased blood flow. This is an advantage if delivery is to an area that is inflamed due to infection. Also in the GI tract, approximately 1-1.5L of blood pass through the capillaries per minute, compared to around 150 ml/minute in the stomach.

Finally the area of absorbing surface is a key factor in drug delivery. Areas such as the lung and the GI tract offer a huge surface over which drug can be absorbed. The intestine, for example, has a surface that is greatly folded, and even the folds posses finger-like projections (page 13 of class notes). The first level of structure is known as the folds of Kerkring. The finger-like projections on the surface of these folds are called villi, and the cells making up the villi have themselves a serrated edge covered in tiny projections called microvilli. These structures serve to increase the surface area by three then 30 then 600 fold, to end up with a total surface area of around 200 m2.

3.2.3. Barriers to Diffusion

Drugs usually pass into the blood steam by diffusion, and then pass to the area of concern by diffusion out of the blood steam into the affected tissue. The drug has to be in solution to diffuse. Aqueous diffusion can take place through either the spaces between cells, known as cell junctions, or through small pores in the capillaries. In order to pass between cells the molecule must be small, with a molecular weight less than 100-150 Daltons. To pass through most capillaries the molecular weight must be less than 20-30,000 Daltons. The exception is in the brain, where the capillary pores are a lot smaller, and the compound must be less than 5000 Daltons.

As mentioned above, drugs can also travel by passing across cell membranes. This is known as lipid diffusion, since the cell membranes are made up of lipophilic substances. This requires the drug to be quite lipid soluble. One way of measuring this parameter is to measure the octanol/ water partition coefficient (Ko/a). A high coefficient indicates a preference for the lipid layer. The Ko/a for insulin is very low, 0.0215. A drug such as phenobarbital, which has a pKa of 7.4, exactly physiological pH, is pretty lipid soluble in acid conditions because of its lack of charge, and is reabsorbed by the kidney into the body. However, if the urine is alkaline, phenobarbital has a charge, and is excreted by the kidney.

Some transport appears to be carrier-mediated, that is special carrier substances take the compound across the membrane. This type of mechanism uses cellular energy and can be saturated or even inhibited. Vitamin B12 is transported across the gut by a compound called transferin, a process that is sometimes refered to as facilitated diffusion and some amino acids are transported into the brain by active transport.

Finally, very large molecules (M.W. > 1000) can enter the cells by a process called pinocytosis, in which the cell membrane forms projections which surround the molecule, which is then engulfed by the cell.