We have already seen that iv injection is special, as it is the only route where no absorption stage is required. As a result of direct application of the dose straight into the blood stream, i.v. administration is also special in being the only route where the entire dose is guaranteed to reach the blood stream i.e. bioavailability must be 1.0 or 100%. For all other routes, there is the potential for incomplete absorption; bioavailability may in practice be 100%, but this can never be guaranteed in the same way that it can with the i.v. route.

Unfortunately, the most commonly used route of drug administration, the oral route, presents the greatest number of obstacles to bioavailability. Below Figure summarizes the potential problems.

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Figure: Mechanisms which may cause oral bioavailability to be incomplete

Figure shows the oesophagus, stomach and intestine. The drug is assumed to be in a solid dosage form (tablet or capsule) that has not yet disintegrated and is shown as a solid black circle in the intestine. The figure also shows blood entering the tissue of the gut via an artery on the left and exiting to the right. This blood does not then follow the pattern seen in most tissues (returning to the right heart), but instead it flows through the liver. Blood exiting the liver finally does the normal thing – flows directly back to the heart. The vessel connecting the gut to the liver is neither an artery nor a vein; it is a ‘portal vessel’ (The Hepatic Portal Vessel — HPV in Fig).

The first potential cause of incomplete bioavailability is that the dosage form may fail to disintegrate and/or allow the active ingredient to dissolve fully. With good formulation, this should not arise, but it needs to be born in mind as a possible problem.

Secondly, there may be breakdown of the active ingredient within the gastrointestinal contents. Three possibilities are particularly obvious:

  • Chemical: The stomach may have a pH as low as 1.0 and some molecules simply cannot withstand this extreme acidity. Without a special enteric coated formulation, such a drug will not be fully orally bioavailable.
  • Enzymatic: The Gastro-Intestinal Tract (CT) contains many digestive enzymes. Any attempt to administer insulin orally, would be doomed to failure, as proteases would digest it.
  • Bacterial: The upper parts of the gut (stomach and small intestine) are normally virtually sterile, so attack by bacteria will not be a problem, so long as the drug is absorbed rapidly enough to have left the gut by the time the GIT contents reach the colon. However, a relatively polar drug such as digoxin is absorbed rather inefficiently and it is likely that a significant part of the dose will still be present when the GIT contents reach the colon. Then the extensive colonic flora will have an opportunity to degrade part of the dose.

 

Thirdly, we have the possibility of incomplete absorption into the blood stream. This is most likely with polar drugs that are very water soluble and lack the required lipid solubility to be efficiently absorbed by passive diffusion. Absorption may also be inhibited by P-glycoprotein efflux. Occasionally absorption may be inhibited by binding of a drug to some other component within the gastrointestinal tract; a classic example being the binding of tetracycline to polyvalent cations (such as Cr in milk), leading to non-absorption of the antibiotic.

Finally, even if a drug molecule survives all these hazards and is absorbed chemically intact into the hepatic portal vessel, it may yet be metabolically eliminated during passage through the liver and never reach the general circulation. Any drug that is metabolized in this way will never be able to exert its pharmacological effect in the body and is not considered to be bioavailable. Such losses are referred to as ‘First pass metabolism’.