Link to 1.1.1.1 Bioavailability and Absorption Teaching Resources
Link to Problems for Discussion


Bioavailability


This is the proportion of administered drug that reaches the systemic circulation (the systemic circulation excludes the portal circulation which takes blood from the gastrointestinal tract to the liver) and is thus available for distribution to the site of action.
Bioavailability is expressed as a percentage and is the amount of drug measured systemically after administration by oral (or transdermal or other routes) compared with the same dose given parenterally (which is considered to be 100% available). The bioavailability of a drug is determined by the extent of absorption and the amount of drug that is subject to pre-systemic metabolism (for orally administered drugs).

Absorption


Absorption means what it sounds like. It is the process of leaving the site of administration (skin, muscle, gastrointestinal tract, lung, etc) and the extent to which this occurs. The most common route of exposure in acute deliberate poisoning is the oral route. Other routes of
exposure include the eye, skin, respiratory tract and parenteral (i.e. injection into a blood vessel)

Initially we will concentrate on factors that are important for drug absorption from the gastrointestinal tract as they have the greatest relevance when considering decontamination. A number of these factors are also important to the movement of drug across other
biological membranes.

Given the charged nature of the gastrointestinal tract’s phospholipid membrane: the ideal drug for rapid absorption would dissolve quickly into small uncharged and lipid soluble molecules.

Influences on absorption

Factors that influence the rate and extent of absorption of a drug from the gastrointestinal tract:
  • Physical and chemical properties of the tablet/suspension/etc as it dissolves and releases the drug:
    • In particular the time for medication dissolution
      • consider the differences between liquid, tablet and controlled release preparations of a medication such as paracetamol. (search for controlled release section in HyperTox)
      • the ingestion of a large number of tablets (eg such as in an overdose) may result in different dissolution characteristics than a single tablet
>
** the solubility of the drug in the acid environment of the stomach
      • the solubility of the drug in the basic environment of the small intestine
>
** Chemical properties which might dictate the type of lumen to blood transfer or the possibility of intestinal wall metabolism
      • Drugs that are poorly lipid soluble, or large or charged may move slowly across a membrane unless the transport is assisted by some active process.

  • The nature of the absorption process: there are 3 main types
    1. Passive Absorption
    • Passive diffusion is a process where drug molecules move from a region of high concentration to a region of low concentration. Therefore, the larger the concentration difference over a finite distance, the faster the drug transport rate. Drug molecules are partitioned into the biological membrane; drug molecules diffuse within the biological membrane; drug molecules partition out of the biological membrane. High permeability is commonly associated with complete and fast absorption whereas low permeability is commonly associated with incomplete and slow absorption.
    • The process is not energy dependent.

  • 2. Carrier-Mediated Absorption
Only a small number (5-10%) of oral drugs are transported by the carrier-mediated process. However, some important classes of drugs are transported this way, including several centrally active amino acid-like drugs (e.g., L-dopa, L-a-methyldopa, and gabapentin), oral b-lactam antibiotics and angiotensin-converting enzyme (ACE) inhibitors. Several classes of future drugs may have structures similar to peptides, nucleosides, and nucleotides, and they are likely to be transported by a carrier-mediated process.
There are two kinds of carrier-mediated transports. One is facilitated and the other is active. The major difference is that the latter uses metabolic energy, mostly in the form of ATP, while the former does not.
    • Active transport introduces a number of variables
      • Genetic variation
      • Competition for the carrier mechanism
      • The possibility of saturation of the mechanism as dose is increased
      • Anatomical localisation of absorption

  • 3. Paracellular Diffusion
Paracellular diffusion is drug transport between the cellular junctions. There are few drugs whose main absorption pathway is paracellular. However, the paracellular pathway contributes to the absorption of many low molecular weight drugs, especially if the drug is hydrophilic (water soluble). The following are a list of general characteristics of paracellular diffusion:
    • Permeability is usually low, typically 5-200 times lower than drugs with good permeability via either passive diffusion or carrier-mediated transport.
    • Permeability does not change with concentration.
    • Permeability does not change with surface area.
    • Molecules have to be small (MW<200), but the rate and extent of absorption is low. Significant paracellular transport only occurs with very small ions (e.g., Na+ and Cl-) and molecules (urea).
    • Paracellular transport is especially sensitive to the effect of chelating agents (e.g., EDTA) that disrupt the tight junction (by binding with Ca++ or Mg++).

  • The rate of gastric emptying and intestinal transit time
    • Although there can be some drug absorption from the stomach most drug absorption occurs after the drug enters the duodenum and small bowel.Some drugs can slow gastric emptying by pharmacological means (eg anticholinergics, opioids) and some by physical means [in overdose some tablets can form large masses (pharmacobezoars)]
    • Gastrointestinal surface area and blood flow to the gastrointestinal tract (which removes absorbed drug and maintains a concentration gradient between the gut and the portal circulation)

Clinicians are mainly concerned the amount of drug that makes it to the systemic circulation or its bioavailability. Bioavailability is a measure that accounts for both the extent of drug absorption combined with the body’s ability to remove drug before it reaches the systemic circulation (first pass metabolism):

First Pass Metabolism

(AKA: FIRST PASS EFFECT, PRESYSTEMIC METABOLISM)
This is the extent of metabolism occurring after the drug is absorbed but before the drug reaches the systemic circulation. Many drugs undergo some metabolism (particularly in the gut wall or liver) prior to reaching the systemic circulation.

see also