Background

The gut is primarily designed for the absorption of nutrients which are presented in a complex and varied matrix comprising protein, carbohydrate, fat, minerals and vitamins in different proportions. The components must be extracted by batch

Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK e-mail: [email protected]

C.G. Wilson and P.J. Crowley (eds.), Controlled Release in Oral Drug Delivery, Advances in Delivery Science and Technology, DOI 10.1007/978-1-4614-1004-1_2, © Controlled Release Society 2011

processing, which involves fluid secretion of liquids providing an optimum milieu for the enzymes to work in a controlled sequence. If a foodstuff is energy rich but difficult to process, motility must be slowed to allow presentation at an appropriate rate with mixing patterns predominating over propulsive activity during digestion. This has to be achieved in the proximal regions of the gut, particularly the jejunum and ileum. At the end of the ileum, secretion is lower and assimilation is the main physiological activity. Finally in the colon water, salts and remaining nutrients must be extracted to conserve the ionic balance of cellular fluids.

The gut of mammals evolved into specialist herbivores, fairly inefficient carnivores and balanced omnivores who were able to take advantage of high calorific densities in flesh and nuts by processing in the fore-gut and to extract significant nutrients from pulverized and enzyme treated vegetables using bacterial populations of the hind-gut. This diversity required a range of enzymes to be available and control of exposure to allow efficient processing. The early diet contained seeds from berries which were poisonous, and nature has preserved protective functions throughout evolution of the mammals to man. Thus we recognize poisonous alkaloids as bitter by taste and have several protective mechanisms to avoid toxin exposure including, in the last resort, vomiting.

Our earliest medicines were derived from plant stuff, and of varied potency. The poor analytical techniques hampered quality control and thus the medicines were dangerous to use. The replacement of plant extracts by chemically synthesized drugs, which were obtained at high purity, and were single entities, made the materials easier to use as pharmacons. Doses of the chemically derived drugs could be relatively large (those which were more potent and hard to detect were still commonly referred to by the public as poisons) and although knowledge of the importance of hepatic metabolism and renal excretion was well established 60 years ago, we knew little of more subtle defense mechanisms. As pharmacological knowledge was refined and medicines became more potent, scientists became aware of protection at the prehepatic, intestinal level including efflux and drug metabolizing systems, which attempt to avoid exposure to xenobiotic materials.

These comments emphasize a couple of important principles which must be always considered. First, the gut is designed to process food and some component of the drug's absorption profile is likely to be affected by the sequence of meals. Second, if the drug concentration is sufficiently low, it may be processed by the protective guardians that reduce exposure.

The basic design of the gut is a long muscular tube with specialized areas for digestion and storage. The plan of the gut is illustrated in Fig. 2.1. As shown, the gut is a long tube supplied by arteries and drained by veins and a lymphatic trunk, all of which are supported in a mesentery, which are folds of the peritoneum attached to the abdominal wall. The small intestine is the major site of nutrient and anutrient absorption. Although uptake occurs in stomach tissue, the contribution of direct gastric absorption to bioavailability is small, and slow delivery into the upper gastrointestinal tract is far more important.

In adults the length of the gut is approximately 7 m and the large intestine 1.5 m in length. Differences in length are apparent at death, when inherent tone is lost.

Fig. 2.1 Illustration of the plan of the gastrointestinal tract showing arrangement of mucosa and muscles

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Measured length (era)

Fig. 2.2 The growth of the human intestine. Measurements made at necropsy. From data of [1]

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Measured length (era)

Fig. 2.2 The growth of the human intestine. Measurements made at necropsy. From data of [1]

A study of 1,010 small intestines at autopsy by Weaver, Austin and Cole was used to construct the data shown in Fig. 2.2 describing the growth of the small intestine to adulthood [1].

Functionally, the gut is divided into a preparative and primary storage region (mouth and stomach), a secretory and absorptive region (the midgut), a water reclamation system (ascending colon) and finally a waste-product storage system (the descending and sigmoid colon). The whole structure loosely fills the abdomen, with the esophageo-gastric junction just below the diaphragm. The pyloric sphincter area and the cardia provide points of attachment and help fix the ends of the stomach; however, when posture changes or the stomach is filled with food, organs such as the stomach can change shape and therefore their position in the abdomen. This generates potential differences in emptying patterns in supine, prone and upright positions.

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