Drug absorption in the small intestine

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". Most often the college will ask about the factors which influence oral absorption (eg. Question 20 from the first paper of 2014 and Question 5(p.2) from the first paper of 2010). As absorption in the small intestine plays a major role in overall oral drug absorption, any discussion of oral dose absorption is by definition a discussion of intestinal transport mechanisms and the factos which affect them.

In summary, drug absorption in the small intestine is influenced by the following major factors:

• Physicochemical properties of the drug (lipophilic drugs and small molecules are absorbed faster)
• Resemblance of the drug to a physiological substrate for active transport proteins (so it might be actively trasnported)
• Surface area of the small bowel
• Duration of intestinal transit
• Intestinal blood flow (though this is usually not a rate limiting step).

Intestinal drug absorption

So, you swallow a tablet. Where will the active ingredient be absorbed, and how long will it take? Will it take effect in time for the dance party? Masaoka et al (2006) explored the absorption of drugs at various sites in the rat bowel. Turns out, pretty much all drug absorption occurs in the small intestine. This is because:

• Drugs spend longer in the small intestine
• The small intestine has a larger surface area

Drug absorption in the intestine can occur by three possible ways:

• Passive diffusion of lipophilic drugs, though the membrane
• Passive diffusion of hydrophilic drugs, through pores and gap junctions
• Active transport of larger molecules by transport proteins

All the pharmacology textbooks seem to have the same fixed idea that the small bowel has a surface area of 200-300m². Where did this number come from? One might imagine some insane experiment where a postgraduate student is asked to lay out hundreds of meters of reeking bilious villi. That tuly might have happened, but the whole truth is probably even weirder.  Gastrointestinal tract area was estimated by some combination of autopsy data and nightmartish  in vivo mapping exercises. In Betty Underhills' 1955 paper, the author refers to Noer and Johnston, 1939: "In their paper a photograph is shown of a patient with the ends of a 10-ft. (3-in.) tube protruding from both mouth and anus." 

Also concerned that the 200-300m² estimate might be some sort of complete bullshit, Helander and Fändriks (2014) took biopsy samples from various parts of the bowel and used these to estimate exactly by how much do these villi increase the surface area of the intestine (turns out, by about 6.5 times in the colon and by 60-100 times in the small intestine ). There is on top of that an increase in surface area by 1.6 times due to the plicae circulares. The average diameter of the small bowel and large bowel are 2.5 and 4.8cm respectively. Then, if one takes into account the variable oroanal length of the gastrointestinal tract in humans, one can use simple maths to work out the surface area of the human digestive tract. Turns out, "the mean total mucosal surface of the digestive tract interior averages ∼32 m², of which about 2 m² refers to the large intestine."

Passive diffusion through the gut membrane

For the vast majority of an orally administered dose of anything, this is the main way of getting into the body. Lipophilic drugs are able to penetrate though cell membranes, whereas water-soluble drugs penetrate through paracellular spaces, moving across the barrier by a combination of concentration-driven diffusion and convective volume flow along with water.

Drug characteristics which favour good paracellular absorption in the intestine are:

• Small molecule (molecular weight < 250g/mol)
• Hydrophilic (ionised at intestinal pH of 5.5-7.0)
• Positively charged (the junctions between cells have a negative charge)

The problems with this manner of transport are:

• Paracellular junctions account for less than 0.01% of the total surface area
• These junctions become less and less permeable as one progresses from jejunum to colon

Therefore, transcellular transport (i.e through the lipid membrane) is the most important form of drug absorption in the intestine.

One of the occasionally encountered barriers to drug absorption in the literature is the "unstirred water layer". This is a 25 μm layer of water at the intestinal lumen. It is mentioned infrequently because it does not appear to play any major role in slow absorption or in reducing its extent. El-Kattan et al (2012) suggests that its contribution is probably insignificant.

Active transport from the gut lumen

Rang and Dale basically brushes this aside by saying that the mechanism of drug absorption from the gut is "passive transfer at a rate determined by the ionisation and lipid solubility of the drug molecules".  However, this is not uniformly the case. For instance, Martinez and Amidon (2002) present a table (Table 1, p. 634) which lists active gastrointestinal transporters and their substrates. It has been reproduced below to simplify revision:

Generally, one can simplify things by assuming that most drugs will be transported actively if they resemble some "natural" substrate chemically. For example, they might appear to be an innocuous amino acid. Thus, drugs like methyldopa and levodopa sneak in through transporters which mistake them for dopa, and 5-fluorouracil is mistaken for uracil. 

Intestinal transit time

Once you're through the pylorus, you have 4-10 hours to get absorbed before you get to the colon. There, the solid content is compacted into lumps, which makes passive diffusion difficult. Realistically, all drug absorption needs to occur in the liquid-filled small intestine.

Fortunately, most drug absorption is rapid and a peak concentration is reached within 30 minutes of administration. One would have to have truly legendary diarrhoea in order for drug absorption to be affected. 

In the normal population, intestinal transit time is usually quite consistent and largely unaffected by gastric emptying. For most people it will be some 2-6 hours. Davis et al (1986) were able to demonstrate that this is not affected by fasting or large meals.

Colonic drug absorption

The colon is a forgotten contributor to drug absorption, even though there is usually about 5m² of surface area there (and so it should contribute to some extent). The major limitations on drug absorption from the colon are:

• Solid stool make diffusion difficult
• Concentration is usually low, as most of the drug has already been absorbed
• Gut bacteria are more numerous, and transit time is slower (i.e. bacterial metabolism is more prevalent)

Effect of splanchnic blood flow on drug absorption

For rapidly absorbed lipophilic drugs, intestinal blood flow may be the rate limiting step. Probably the only drugs absorbed fast enough for this to be an issue are ethanol or methanol. in contrast, in critical illness intestinal blood flow might be so poor that it will be the rate-limiting step for many or all drugs.