Drugs taken orally for systemic effects have variable absorption rate and variable serum concentrations which may be unpredictable. This has led to the development of sustained-release and controlled-release systems.
The high acid content and ubiquitous digestive enzymes of the digestive tract can degrade some drugs well before they reach the site of absorption into the bloodstream, which is a problem for ingested proteins. Therefore, this route has limitations for administration of biotechnology products.
Many macromolecules and polar compounds cannot effectively traverse the cells of the epithelial membrane in the small intestines to reach the bloodstream. Their use is limited to local effect in the gastrointestinal tract.
Many drugs become insoluble at the low pH levels encountered in the digestive tract. Since only the soluble form of the drug can be absorbed into the bloodstream, the transition of the drug to the insoluble form can significantly reduce bioavailability.
The drug may be inactivated in the liver on its way to the systemic circulation. An example of this is the inactivation of glyceryl trinitrate by hepatic monooxygenase enzymes during the first-pass metabolism.
Some drugs irritate the mucous lining of gastrointestinal tract, which is counteracted to some extent by coating.
Oral route may not be suitable for drugs targeted to specific organs.