The gastrointestinal tract is complex. Figure 1 outlines some of the main structures involved in and key physiological parameters that affect oral drug absorption.
In order to gain an insight into the numerous actors that can potentially influence the rate and extent of drug absorption into the systemic circulation, a schematic illustration of the steps involved in the release and absorption of a drug from a tablet dosage form is presented in Figure 2.
It can be seen from this that the rate and extent of appearance of intact drug in the systemic circulation depend on a succession of kinetic processes.
The slowest step in this series, which is the rate limiting step, controls the overall rate and extent of appearance of intact drug in the systemic circulation. The rate-limiting step will vary from drug to drug.
For a drug which has a very poor aqueous solubility, the rate at which it dissolves in the gastrointestinal fluids is often the slowest step and the bioavailability of that drug is said to be dissolution rate limited.
In contrast, or a drug that has a high aqueous solubility, its dissolution will be rapid and the rate at which the drug crosses the gastrointestinal membrane may be the rate-limiting step termed permeability limited.
Other potential rate-limiting steps include the rate of drug release from the dosage form (this can be by design, in the case of controlled-release dosage forms), the rate at which the stomach empties the drug into the small intestine, the rate at which the drug is metabolized by enzymes in the intestinal mucosal cells during its passage through them into the mesenteric blood vessels, and the rate of metabolism of drug during its initial passage through the liver, often termed the ‘first-pass’ effect.