Anatomical and physiological parameters affecting gastrointestinal absorption in humans and rats

doi:10.1016/S0278-6915(00)00136-8

Food and Chemical Toxicology

Volume 39, Issue 3, March 2001, Pages 209-228

https://doi.org/10.1016/S0278-6915(00)00136-8 Get rights and content

Abstract

Anatomical and physiological parameters of the gastrointestinal (GI) tract dramatically affect the rate and extent of absorption of ingested compounds. These parameters must be considered by nutritionists, pharmacologists and toxicologists when describing or modeling absorption. Likewise, interspecies extrapolation (e.g. from rat to human) requires species-to-species comparison of these parameters. The present paper (1) describes the alimentary canal and the barrier to absorption; (2) relates the major sites of absorption; (3) compares the dimensions and surface areas of human and rat intestinal tracts; (4) discusses motility of the gut and transit times through regions of the alimentary canal; (5) explains how luminal contents are altered by physical, chemical and metabolic processes; and (6) describes the flow of blood and lymph from the GI tract to the systemic circulation, including the enterohepatic circulation. Despite strong morphological similarities between humans and rats at the microscopic level, gross anatomical differences in the relative absorptive surface areas provide a basis for concluding that the human GI tract is capable of absorbing materials faster and to a greater extent than that of the rat. Differences in the environment of the GI lumen of the two species make it possible to infer which substances are more likely to be present in a dissolved/non-ionized state for each species. Taken together, these differences may be of sufficient magnitude to alter the assessment of risks/benefits for a given compound when those risks/benefits are based on interspecies extrapolations.

Introduction

Scientists from many disciplines need to understand how orally administered compounds enter the body. Nutritionists want to know how nutrients are extracted from food and absorbed so they may be used by the body. Pharmacologists design drug formulations to optimize absorption and thereby blood levels of a pharmaceutical. Toxicologists are interested in the extent to which xenobiotics enter the body and become available to (adversely) affect it. Information about absorption is necessary to model and predict the kinetics of a compound within a given species or to extrapolate between species (e.g. from rats to humans). Physiologically-based pharmacokinetic models and biologically motivated models are valuable tools for such modeling, predicting and extrapolating, but they require quantitative, as well as qualitative, knowledge about the biological systems under study.

Many factors influence a chemical's rate and extent of absorption after oral intake (Aungst and Shen, 1986, Rozman and Klaassen, 1996). These may be readily categorized into factors that are inherent either to the agent or to the absorptive interface of the animal species under study. Physicochemical properties of a compound are perhaps most important; these include the lipophilicity, ionization state and molecular size of a chemical. These properties are independent of the test species. Absorption also can be greatly affected by other materials present in the gastrointestinal (GI) tract; those other materials can be the vehicle (solvent) used in a laboratory experiment or the food eaten prior to or concomitantly with the ingestion of the chemical. While these factors depend upon the diet of the test species, they are largely physical and chemical factors that are readily modeled. Perhaps the most enigmatic properties that affect absorption, and the ones that cause the greatest interspecies differences, are those that are specific to the test organism: the anatomy and physiology of the GI tract.

The GI tract of humans has many morphological similarities with those of most test species, especially at the level of microscopic observation (Iatropoulos, 1986). The body of research that has revealed how lipids cross the intestinal epithelium, how proteins and carbohydrates are processed, and many of the details regarding the activity of intestinal hormones and digestive enzymes in humans was generated using animal models. Despite these strong interspecies similarities, there are significant differences among species with regard to the amounts and locations of absorptive epithelia, as well as the nature of luminal contents. These differences are likely to play an important role in the degree to which drugs or toxicants are absorbed and in the rate of uptake of such substances. Both are important to consider when describing pharmaco/toxicokinetics or when developing physiologically-based pharmacokinetic models.

Although the specific features of the GI tract may be critical determinants of absorption, their significance is often overlooked. This paper provides an overview of the digestion and absorption processes occurring within the alimentary canal and focuses on those anatomical and physiological features that are important to absorption of nutrients and non-nutrients in humans and rats.

Section snippets

General description of the alimentary canal

The alimentary canal (Fig. 1) is essentially an open-ended, epithelium-lined tube that extends from the mouth to the anus. Entry into the body proper requires traversing the epithelium and eventually entering the systemic circulation. When viewed in such a manner, it becomes clear that the lumen and its contents are considered to be outside the body proper: the lumen can be conceptualized as a tunnel of the environment through the body, and the wall of the alimentary canal as the interface

The nature of the barrier to absorption

From the mouth to the anus, the alimentary canal is lined with a mucous membrane, or mucosa, that serves as the first barrier to entry of materials into the body. The mucosa is composed of an epithelial sheet overlying a thin layer of loose connective tissue (lamina propria) that contains both blood and lymphatic capillaries. Absorption of a substance from the lumen of the alimentary canal usually requires that the substance pass through the epithelium, a portion of the lamina propria, and the

Sites of absorption

While the systemic absorption of orally ingested materials takes place mainly in the small and large intestines (particularly in the duodenum and proximal jejunum), absorption can and does take place at other sites along the alimentary canal as well. The most important non-intestinal site of absorption is the stomach, which is capable of absorbing non-ionized, lipophilic molecules of moderate size. However, absorption there is limited by the relatively small epithelial surface area and the

Dimensions and surface areas of the intestinal tract

The primary site of absorption of substances from the lumen of the alimentary canal is the intestinal tract. A comparison of the dimensions of the intestinal tract would therefore seem to be a logical first step in comparing GI absorption in humans and rats. That task, however, is not easily accomplished. There exist few readily accessible sources of such data for the rat, while the more abundant data for the human vary widely. Table 1 indicates the diversity of information related to the

Motility and transit time

Most of the alimentary canal of both humans and rats is surrounded by at least two layers of smooth muscle. The muscle fibers of the inner layer are arranged circumferentially relative to the lumen; those of the outer layer are arranged parallel to the long axis of the canal. The co-ordinated, rhythmic contractions of these layers of smooth muscle cause the intestinal motility which is responsible for the thorough mixing of chyme, the continual rejuxtaposition of chyme with the brush border of

The nature of luminal contents

The nature of the luminal contents in both humans and rats is altered as the contents traverse the alimentary canal. This alteration is due to (1) the physical dispersion of ingested solid matter by chewing and the muscular activity of the stomach, coupled with the mixing of the ingested matter with imbibed fluid and digestive juices; (2) the action of enzymes on GI contents; (3) the absorption of fluid and materials from the lumen; and (4) the addition of bacterial flora to the contents. Each

Blood and lymph flow

The tissues of the human and rat alimentary canals, like other tissues of the body, contain vessels of both the blood and lymphatic vascular systems. The absorbed material that is transported by both the blood and lymphatic vessels passed through the enterocytes to gain access to the interstitial fluid of the lamina propria. This interstitial fluid has a dual origin: it is derived both from the fluid that passes out of the lumen of the alimentary canal and also from an exudate of plasma

Enterohepatic recirculation

The hepatic portal system of both humans and rats is comprised of blood flow from the capillaries of the small intestine, through the tributaries of the hepatic portal vein, to the sinusoids of the liver without traversing the heart. Venous blood from the small intestine, which carries absorbed substances, is said to have undergone enterohepatic circulation when it has traversed this route. Once in the liver, many absorbed substances are removed from the blood by the liver parenchymal cells and

Conclusion

Several parameters require consideration in any attempt (1) to define and model the events involved in GI absorption of nutrients and non-nutrients and (2) to extrapolate the results of these efforts between species. These include anatomical and physiological features of the GI tract (surface area, vascularity, transit time/motility, and enterohepatic recirculation), as well as physicochemical properties of the chemical under study and of the GI contents. Variations in these parameters among

Acknowledgements

The authors are indebted to Ms Elaine Mullen for her meticulous attention to detail in the multiple iterations during creation of the figures and to Mr Michael Yang for his assistance in refining the figures to final form. The authors also thank Dr Richard Mavis for his advice in the planning of this project and his stimulating critiques of our early drafts. This work was supported by the US Air Force Armstrong Aerospace Medical Research Laboratory and the Mitretek Biomedical Research Institute.

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ReviewAnatomical and physiological parameters affecting gastrointestinal absorption in humans and rats