If the lumen of the small intestine is occluded by inflating a balloon a short distance below the pyloric sphincter, the plasma levels of glucose from a glucose drink are reduced when compared to levels obtained with free transit of the liquid36. Experiments of this type allowed an estimate to be made of the length of intestine required to absorb a particular material. Many nutrients are absorbed almost completely by the time the meal reaches a point 100 cm from the pylorus73. This formed the basis of the hypothesis that absorption of the drug from a particular formulation was completed in the upper part of the small intestine, and the remaining length was a "reserve", i.e. unused for drug absorption74. If the reserve length was long, this implied that the drug was rapidly absorbed.
In this model the reserve length is defined as the distance from the point at which 95% of the drug has been be absorbed (the absorption length), to the distal end of the small intestine. The drug concentration is assumed to decline continuously with distance from the pyloric sphincter as absorption takes place. If the absorption length is similar to the total intestinal length, then RL approaches zero and the drug will be completely absorbed. The choice of 95% absorption is arbitrary. This hypothesis may apply to some drugs, but it assumes that small bowel contents move down the small intestine at a relatively constant rate and that there are no differences in absorptive capacity along the gastrointestinal tract. This theory is also incorrect from a number of standpoints; there is considerable mixing in the small intestine and individual particles of food can move at independent and widely differing rates. Moreover, values for the median transit times of the same components of a meal in different subjects can show considerable variability. The liquid meals used in the earlier study contained nutrients which could be rapidly assimilated because they were in a simple and well-dispersed form. The intestinal reserve length theory would not necessarily apply to normal meals which are complex and semisolid. Analysis of the effluent from ileostomies, for example, shows that quite high proportions of ingested nutrient enter the terminal ileum. Studies in man and in experimental animals have shown that food may move more rapidly through the jejunum to collect in the lower ileum from where residues are propelled at a more gradual rate to the colon. Thus, it seems likely that most of the small intestinal length is used for the absorption of drugs, particularly when these are given with a meal, and the concept of small intestinal reserve length is not a generally applicable guide to bioavailability. This concept also cannot be applied to certain drugs which are incompletely absorbed; for example the b-blocker atenolol which is absorbed for 3-4 hours following administration. Absorption then stops abruptly, even though 50% of the dose remains unabsorbed, possiblyon entry of the drug into the colon, where it is not absorbed. Similarly hydrochlorothiazide is poorly absorbed in the colon75 and hence absorption stops abruptly as the bolus enters this region. Although intestinal reserve length is a useful guideline, it makes a number of physiological assumptions, primarily that there is no variation in the absorptive capacity of the small intestine along its length. This assumption may be true for some materials, but in other cases absorption may be carrier-mediated or occur at specific sites.
An alternative approach to the intestinal reserve length theory uses the calculation of the drug dissolution under sink conditions together with physiological variables such as the rate of gastric emptying76. The degree of absorption of a drug from the small intestine is directly related to the length of time that the drug remains in contact with the absorptive epithelium. Utilising measurements of drug dissolution under sink or non-sink conditions as appropriate, the time taken for the drug to be released from the formulation, i.e. disintegration and dissolution, can be calculated. This should be less than, or equal to the combined time available for absorption and transit through the potential absorption window in the small intestine. The latter terms will be highly influenced by the degree of colonic absorption since, in the absence of absorption from the proximal colon, only a maximum of 3-5 hours is available for absorption from the small intestine in the fasting state. Absorption from the proximal colon affords a further six hours of contact time. This model would predict a marked increase in bioavailability for formulations of poorly absorbed drugs such as frusemide taken with a heavy meal since the meal provides a slow input into the upper small intestine, the major site of absorption (Figure 6.14).
Was this article helpful?
Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...