Factors Which Influence Gastrointestinal Drug Absorption

This chapter answers parts from Section B(ii) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "Describe absorption and factors that will influence it". Specifically, this chapter deals with gastrointestinal absorption which seems to be important, not only because it is a common route of drug administration but also because it has appeared at least once in the written CICM Primary paper.

Question 20 from the first paper of 2014 asked about the factors which might affect gastrointestinal absorption. According to the college answer, a bare minimum pass answer could have been generated by the invocation of "basic principles" and being able to "think on the fly", which has an uncharacteristically ad-hoc sound to it. The college answer did not elaborate very far beyond that. One is left to imagine that the marking criteria would have included an elaborate and detailed overview, but for whatever reason the examiners chose not to share this with the future candidates.

As far as literature goes, this topic is somewhat undersupplied by the recommended textbooks. The gastrointestinal absorption section of Goodman and Gilman leaves much to be desired. Fortunately, Martinez and Amidon (2002) do an excellent overview of the factors which affect intestinal drug absorption, and this article still seems to be available for free. A slightly dated article by Orme (1984) could also act as a stand-alone resource for pre-exam reading, and was used top. If one were able to get hold of it, the most detailed overview of this subject can be found in "Drug absorption from the gastrointestinal tract" - Chapter 5 (p87) from Basic Pharmacokinetics, by Jambhekar and Breen. 

Drug absorption from the gastrointestinal tract

Rang and Dale basically brushes this aside by saying that "the mechanism of drug absorption is the same as for other epithelial barriers, namely passive transfer at a rate determined by the ionisation and lipid solubility of the drug molecules".  In essence, what the authors were trying to say was that the same physicochemical factors influence gut membrane transport as influence transport across all the other membranes. This is of course not surprising but it still needs to be mentioned. Instead of elaborating extensively on exactly what those factors are, a link is offered to the chapter which discusses them in detail.

In general, this revision topic was originally planned as a single-chapter summary, but developed into something rather monstrous and had to be dismembered. Now, it is fragmented into many smaller chapters, which hopefully render the content less daunting. Links to these chapters were integrated into the table below. 

Thus, in summary, the factors which influence the absorption of drugs from the gastrointestinal tract are as follows:

Factors which Influence Drug Absorption from the Gastrointestinal Tract

Drug factors: 

  • Concentration

A large drug dose will be absorbed more rapidly because of the high concentration gradient

  • Molecule size

Small molecules diffuse more easily

  • pKa

Weak acids are better absorbed; lipophilic drugs are better absorbed

  • Tablet disintegration

Stability of the tablet determines the dispersion rate of the drug, and therefore the rate of absorption. This is manipulated intentionally in slow release formulations

  • Particle size

The smaller the particles, the greater the surface area from which the drug will be eluted

   
Gastrointestinal factors

Gastric emptying is the major determinant of absorption

  • Intestinal motility

Intestinal motility can increase or decrease absorption (eg. slow gut transit can ensure complete absorption of a drug bezoar)

  • Splanchnic perfusion

Gut perfusion is a rate-limiting step in drug absorption only for rapidly absorbed drugs, but as perfusion slows it also becomes more important for all other drugs.

  • Surface area

Surface area of the small intestine is massive (usually, tens of square metres) and this increases absorption. Factors which decrease intestinal surface area (eg. denuded villi due to gastroenteritis, or surgacal short gut) will decrease drug absorption

  • Mode of transport

Drugs can be transported by passive diffusion (either paracellular or transcellular); some are actively transported out of the gut lumen, and others may be actively excreted back into it by efflux pumps.

  • Intestinal content

Interaction with other drugs and food substances (eg. tetracycline chelating intestinal calcium from milk, thereby forming an insoluble complex which defeats absorption) 

  • Bile and bile salts

The emulsifying effect of bile is critical to the absorption of fat-soluble vitamins and steroids

  • Enterohepatic recirculation

Some drugs may be eliminated in the bile only to be reabsorbed in the jejunum

  • Gut bacteria

Gut bacteria may either deactivate drugs (by metabolisng them) or activate drugs (by metabolism of an inactive precursor). 

  • Metabolism in the intestinal wall

Enterocytes may metabolise drugs before they undergo first-pass metabolism. Injured enterocytes (eg. after ischaemia) may lose their metabolic function.

Absorption and bioavailability are different concepts. One might be asked about the factors which influence the bioavailability of orally administed drugs, which - as well as absorption - would have to factor in first pass metabolism.

 

References

Welling, Peter G. "Influence of food and diet on gastrointestinal drug absorption: a review." Journal of Pharmacokinetics and Biopharmaceutics 5.4 (1977): 291-334.

Levine, Ruth R. "Factors affecting gastrointestinal absorption of drugs." Digestive diseases and sciences 15.2 (1970): 171-188.

Prescott, L. F. "Pathological and physiological factors affecting drug absorption, distribution, elimination, and response in man." Concepts in Biochemical Pharmacology. Springer Berlin Heidelberg, 1975. 234-257.

Martinez, Marilyn N., and Gordon L. Amidon. "A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals." The Journal of Clinical Pharmacology 42.6 (2002): 620-643.

Chillistone, Shruti, and Jonathan G. Hardman. "Factors affecting drug absorption and distribution." Anaesthesia & Intensive Care Medicine 18.7 (2017): 335-339.

Hogben, C. Adrian M., et al. "Absorption of drugs from the stomach. II. The human." Journal of Pharmacology and Experimental Therapeutics 120.4 (1957): 540-545.

Schanker, L. S. "Absorption of drugs from the gastrointestinal tract." Concepts in Biochemical Pharmacology. Springer Berlin Heidelberg, 1971. 9-24.

BERGGREN, SVEN M., and LEONARD GOLDBERG. "The Absorption of Ethyl Alcohol from the Gastro‐Intestinal Tract as a Diffusion Process." Acta Physiologica 1.3 (1940): 246-270.

Schanker, Lewis S., et al. "Absorption of drugs from the stomach I. The rat." Journal of Pharmacology and Experimental Therapeutics 120.4 (1957): 528-539.

Mitra, Amitava, and Filippos Kesisoglou. "Impaired drug absorption due to high stomach pH: a review of strategies for mitigation of such effect to enable pharmaceutical product development." Molecular pharmaceutics 10.11 (2013): 3970-3979.

Masaoka, Yoshie, et al. "Site of drug absorption after oral administration: assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract." European journal of pharmaceutical sciences 29.3 (2006): 240-250.

Orme, M. "Drug absorption in the gut." BJA: British Journal of Anaesthesia56.1 (1984): 59-67.

Helander, Herbert F., and Lars Fändriks. "Surface area of the digestive tract–revisited." Scandinavian journal of gastroenterology 49.6 (2014): 681-689.

Underhill, Betty ML. "Intestinal length in man." British medical journal 2.4950 (1955): 1243.

El-Kattan, Ayman, and Manthena Varma. "Oral absorption, intestinal metabolism and human oral bioavailability." Topics on drug metabolism. InTech, 2012.

Davis, S. S., J. G. Hardy, and J. W. Fara. "Transit of pharmaceutical dosage forms through the small intestine." Gut 27.8 (1986): 886-892.

Cummings, J. H., and G. T. Macfarlane. "Role of intestinal bacteria in nutrient metabolism." Clinical nutrition 16.1 (1997): 3-11.

Mikov, M. "The metabolism of drugs by the gut flora." European journal of drug metabolism and pharmacokinetics 19.3 (1994): 201-207.

Roberts, Michael S., et al. "Enterohepatic circulation." Clinical pharmacokinetics 41.10 (2002): 751-790.

Rouge, Nathalie, Pierre Buri, and Eric Doelker. "Drug absorption sites in the gastrointestinal tract and dosage forms for site-specific delivery." International journal of pharmaceutics 136.1-2 (1996): 117-139.