By Duy Thai: www.geocities.com/d.

thai 1997 Pharmacology Semester 1 page 1 of 3

DRUG ABSORBPTION

Drug absorption

• In order for a drug to be absorbed, it must be able to pass through cell membranes (which is a lipid barrier).
Lipid soluble drugs would be ideal to pass through the membrane easily, but not all drugs can be lipid soluble
to a great extent. There are 4 main ways drugs can be absorbed:
1. Lipid diffusion
2. Aqueous diffusion
3. Coabsorption with lipids
4. Facilitated diffusion/active transport

Lipid diffusion
• Highly lipid soluble drugs are able to pass across cell membranes quite easily. The movement is driven by
passive diffusion down a concentration gradient.
• The lipid partitioning coefficient is a numerical value of how lipid soluble a drug is.
P=
[lipid ]
[H 2 O]
• If the concentration of the drug is higher in a lipid medium than in an aqueous medium, it will have a high P
and hence have a high lipid solubility.

Aqueous diffusion
• There are such things as aquaporins – special protein channels designed for the movement of water into and
out of cells. Drugs which are small and easily dissolved in solution will be able to pass through the cell
membrane via this route, in conjunction with water which naturally diffuses.

Coabsorption with lipids

• Some drugs can be absorbed in conjunction with lipids via micelles. E.g. Vitamin A, digitoxin.
• A micelle is formed with the drug incorporated into its structure. Therefore, when the micelle is absorbed, so
is the drug.

Facilitated diffusion/active transport

• All cells have specialised transport systems and channels which allow the active (requiring energy) uptake of
materials from the ECF into the cell. These materials are often nutrients required by the cell. If a drug is
structurally similar to the compound a transport system normally takes up, the drug will be able to enter the
cell by making the cell think it is someone else. E.g. Levadopa (used to treat Parkinsons) is taken up via the
aromatic amino acid transport system.

Features of drugs which affect their absorption

• Molecular weight
• Drugs with a small size are absorbed well
• Drugs which are large (often proteins) are absorbed poorly. These drugs are often administered
intravenously to avoid any absorption barriers.
• Chemical and enzymatic stability
• The drug must be able to withstand the acid conditions in the stomach and also the gut enzymes. E.g.
Penicillin G (a β lactam antibiotic) is highly acid labile, which means that it is not stable to acid.
• Aqueous and lipid solubility
• A drug cannot be totally lipid soluble, otherwise it would not be able to dissociate in the circulation
to remain in solution. On the other hand, we don’t want a drug to be totally soluble because it may
have problems in absorption. What is needed is a balance between these 2 properties.

pH and lipid solubility

• Most drugs are either weak acids or weak bases and can exist in either the ionised (less lipid soluble) or unionised
(more lipid soluble) form, depending on the pH of the surrounding environment.
• Acidic drugs have a carboxylic functional group (- COOH)
• Basic drugs have an amine group (-NH2)
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 2 of 3

Ionisation constants are given by :

• For acids: FOR ACIDS FOR BASES
• A-H ⇔ A- + H+
Ka =
[A ][H ]
− +
Ka =
[B][H + ]
• For bases:
• BH+ ⇔ B + H+
[AH ] [BH ]+

log
[Unionised ] = pKa − pH log
[Unionised ] = pH − pKa
[Ionised ] [Ionised ]
• The ionisation constants give an indication of how strong the acid is. If Ka is large (and hence pKa is small), then
at equilibrium, more of the acid will exist in the ionised form.
• The opposite can be said for bases. If pKa is small for a base, then at equilibrium, more of the base will be in the
unionised form. Hence a stronger base will have a large pKa rather than a small one.
• If an acid drug lives in an acid environment, then the proton which it has (the H+) will be retained and it will exist
preferably in its unionised form.
• If pH = pKa: Equal amounts of the ionised and unionised forms
• If pH < pKa: More of the drug is in the unionised form
• If pH > pKa: More of the drug is in the ionised form
• If a basic drug lives in a basic environment, then it will not want to accept a H+ and so it will exist preferably in its
unionised form.
• If pH = pKa: Equal amounts of the ionised and unionised forms
• If pH < pKa: More of the drug is in the ionised form
Note how it is opposite to acid drugs
• If pH > pKa: More of the drug is in the unionised form

• REMEMBER THAT A DRUG IS ABSORBED BETTER IN THE UNIONISED FORM

• e.g. Aspirin is an acidic drug. In the stomach, the pH is from 1 - 3, which means that it is an acidic environment.
Hence most of the drug will exist in the uinionised form and be better at passing through the lipid membranes (i.e.
better absorbed - around 30% of the oral dose, the rest is absorbed in the small intestine). Do not confuse this with
the solubility of aspirin. A drug in the ionised form is better soluble but not necessarily better absorbed.
• Remember that the majority of a drug is absorbed in the small intestine, but acidic drugs also have a
relatively large proportion of their concentration absorbed in the stomach
• On the other hand, basic drugs such as MIPRAMINE (an antidepressant), has 100% absorption in the
small intestine.

pH changes in the gut

• There is a 106 fold change in the pH as we move from the stomach to the small intestine:
• Stomach pH: 1-3
• Duodenum pH: 5
• Small intestine pH 5-7

Factors affecting gastrointestinal absorption

• Gastrointestinal contents
• Have you eaten yet? Generally, an empty stomach = better absorption since some drugs may interact
with food.
• Gastric retention time
• Drugs which are well absorbed from the small intestine (e.g. ethanol) will benefit from an increased
gastric emptying rate since more of the drug will be ejected from the stomach into the small intestine.
• Intestinal transit, GIT motility????????????????
• First pass effect
• Blood supply from the gut goes directly to the liver via the portal vein. Therefore, orally absorbed drugs
will reach the liver before entering the systemic circulation. This will be bad if the drug is heavily
metabolised by the liver, which in most cases inactivates the drug.

Bioavailabilty
• The amount of drug reaching its site of action
• If a drug is administered intravenously, then the bioavailability will be 100% (provided we want the drug to be
present in the plasma)
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 3 of 3

• The bioavailability can be much less for other routes of administration.

• e.g. 500µg of a drug is administered but only 100µg enters the circulation. That means 400µg is lost
(wasted) in bodily excretions.
• Factors affecting bioavailability:
• Incomplete absorption
• See the factors which affect absorption above
• First pass effect
• You should know what this is by now
• Enterohepatic shunt
• Lipid soluble drugs can make their way into bile and be excreted along with it. The drug can be
excreted with the bile or reabsorbed with some bile which is reabsorbed via the enterohepatic
circulation.