Define bioavailability (10% of marks). Outline the factors which affect it (90% of marks).

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College Answer

Many candidates spent time defining and describing aspects of pharmacokinetics which were not relevant to the question. E.g. clearance, volume of distribution and half-life. Candidates who scored well utilised a structure which incorporated the headings of the factors which affect the bioavailability of medications with a simple description as to the nature of the effect. These factors included: the physical properties of the drug, the preparation, patient factors, the route of administration and metabolism amongst others.

Discussion

  • Bioavailability is the fraction of the dose which reaches systemic circulation intact
    • IV bioavailability is by definition 100%
    • "Absolute" bioavailability compares one non-IV route with IV administration. 
    • "Relative" bioavailability compares one non-IV route or formulation with another (instead of using IV route as a reference).
    • Bioavailability is measured using the area under the concentration-time curve (Dost's Law). The ratio of AUCs is the bioavailability value.
Factors which Influence Drug Bioavailability

Generic influences on drug bioavailability

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

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

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
  • First pass metabolism

Bioavailability via transdermal and mucosal routes of administration

  • Mucosal blood flow
  • Drug lipophilicity
  • Factors affecting membrane penetration, eg. molecule size, pKa, etc
  • pH of the mucosal fluid

References

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.

De Paepe, Peter, Frans M. et al  "Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock."  Clinical pharmacokinetics 41.14 (2002): 1135-1151.