Question 5(p.2)

With regard to ORAL drug dosing, describe the factors that affect the fraction of drug reaching the systemic circulation (80% marks). How may these factors be altered in a patient with shock (20% marks)?

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College Answer

For a good answer candidates were expected to define bioavailability and the factors 
that affected a drugs oral bioavailability. This was often overlooked by candidates. 
For example, factors affecting absorption (Metabolism by gut flora, drug / drug 
interactions with in the gut, lipophilicity and hydrophilicity of the drug (drug that are 
markedly lipophilic or hydrophilic cross the mucus layer or villous membrane poorly), 
First Pass clearance and sites and mechanism of possible metabolism, to define 
hepatic clearance, extraction ratio (providing a formula proved helpful to many 
candidates) and factors that affected hepatic drug clearance. Candidates often 
lacked an understanding of this area, or failed to mention it. In relation to the second 
part of the question, candidates were expected to mention the effects of reduced 
absorption and altered first pass metabolism resulting in uncertain bioavailability of 
oral drugs. 
Syllabus: Section II, 2a, b
References: Pharmacology, Rang, Ritter and Dale, Chp 7. Goodman and Gilman's 
the Pharmacological Basis of Therapeutics, Chp 1


It is weird that the college wanted a definition of bioavailability in their model answer, when they themselves had paraphrased that definition in the question. The definition of bioavailability according to Birkett et al (2009):

"Bioavailability is the fraction of the dose which reaches systemic circulation as intact drug"

This one is from Pharmacokinetics Made Easy, which is the official pharmacokinetics text of the CICM primary exam. A better definition from the FDA, created by consensus of pharmacologists, reads "bioavailability is the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action". But that doesn't really roll off the tongue, and is harder to remember.

Factors which affect bioavailability include:

Generic influences on drug absorption

  • Drug concentration at site of administration
  • Surface area of the absorptive site
  • Drug pKa
  • Drug molecule size
  • pH of the surrounding fluid

Factors affecting gastrointestinal absorption

  • Gastric motility
  • Intestinal motility
  • Splanchnic perfusion
  • Tablet disintegration
  • Mode of transport
  • Intestinal content
  • Bile and bile salt content
  • Enterohepatic recirculation
  • Metabolism by gut bacteria
  • Metabolism in the intestinal wall
  • Drug on drug interactions in the gut

Factors affecting first pass metabolism

  • Drug absorption from the gut
  • Drug metabolism in the gut
  • Metabolism in the gut wall
  • Metabolism in bloodstream (eg. plasma esterases)
  • Hepatic blood flow
  • Hepatic enzyme activity
  • Spontaneous drug degradation

The effect of shock on these factors:

  • Oral administration may be impossible (unconscious patient)
  •  Gastric motility is diminished, emptying is delayed
  • Intestinal motility is diminished
  • Splanchnic perfusion is decreased
  • There may be no intestinal content (nil by mouth)
  • Bile and bile salt content of the gut will be decreased (fasted patient)
  • Metabolism by gut bacteria may be increased (gastric stasis) or decreased (due to the use of broad-spectrum antibiotics)
  • Metabolism in the intestinal wall may be impaired (decreased perfusion, downregulation of enzymes, gut ischaemia)
  • There may be increased absorption of the drug by diffusion as the ischaemic gut wall loses its barrier function
  • First pass metabolism may be impaired by hepatic ischaemia or poor hepatic / portal blood flow
  • Bloodstream enzymes responsible for drug degradation may be diminished in concentration due to downregulation of their synthesis as part of the the acute phase response
  • Bioavailability of circulating drugs may be increased by decreased synthesis of binding proteins (eg. hypoalbuminaemia of acute illness)


Wesch, Roland. "Absolute and relative bioavailability." Drug Discovery and Evaluation: Methods in Clinical Pharmacology. Springer Berlin Heidelberg, 2011. 173-180.

Vaughan, D. P. "A model-independent proof of Dost's law of corresponding areas." Journal of pharmacokinetics and biopharmaceutics 5.3 (1977): 271-276.

Branson, Herman. "The kinetics of reactions in biological systems." Archives of biochemistry and biophysics 36.1 (1952): 48-59.

Dost, F. H. "Absorption, Transit, Occupancy und Availments als neue Begriffe in der Biopharmazeutik." Journal of Molecular Medicine 50.8 (1972): 410-412.

Balant, L. P. "Is there a need for more precise definitions of bioavailability?." European Journal of Clinical Pharmacology 40.2 (1991): 123-126.

Rescigno, Aldo. "Bioequivalence." Pharmaceutical research 9.7 (1992): 925-928.

Koch-Weser, Jan. "Bioavailability of drugs." New England Journal of Medicine 291.10 (1974): 503-506.

Allam, Ahmed N., S. S. El Gamal, and V. F. Naggar. "Bioavailability: A pharmaceutical review." Int J Novel Drug Deliv Tech 1.1 (2011): 77-93.

Pond, Susan M., and Thomas N. Tozer. "First-pass elimination basic concepts and clinical consequences." Clinical pharmacokinetics 9.1 (1984): 1-25.