Intubation Techniques for the Study of the Absorption of Drugs in Man

Summary

Intubation techniques have been used for several decades to investigate digestive processes in man. They became quantitative when non-absorbable markers were introduced. Later on multichannel tubes made it possible to perform simultaneous measurements at different levels in the gastrointestinal tract. We are using them since 1981 to explore the absorption of drugs from the stomach to the colon. Different variants of the method have been necessary to explore the different levels of the gastrointestinal tract.

Gastric, duodenal and upper jejunal absorptions were determined simultaneously. A tube was placed in the stomach and three others in the small intestine; one at the level of the papilla, the second at the angle of Treitz and the third 30 cm further down. The studied drug (metoprolol) was introduced in the empty stomach with a liquid meal containing ¹⁴C-PEG 4000. A solution of unlabelled PEG 4000 was perfused at a constant rate below the pylorus. Luminal samples were collected at intervals in the stomach, at the end of the duodenum and in the jejunum.

To investigate ileal absorption, a multichannel tube with an inflatable balloon was used which prevented digestive secretions reaching the studied segment. One nonabsorbable marker was added to the drug solution in saline. Absorption rates in the ileum were compared to those in the jejunum in the same subjects on two different days by allowing the tube to spontaneously move from jejunum to ileum. Colonic absorption could not be studied directly. A simple comparison between the plasma profiles obtained in the same subjects when a drug solution was infused at a constant rate either in the jejunum or in the colon was performed.

These investigations demonstrated that metoprolol is absorbed at similar rates all along the gastrointestinal tract. In addition these investigations revealed that food, but not digestive secretions, increases the absorption rate. They provided interesting findings about the physiological effects of metoprolol. These studies demonstrated the validity of the intubation techniques to investigate drug absorption in humans. Nevertheless, they are extremely time consuming and require the collaboration of well trained gastroenterologists.

Most drugs are given orally, but little is known about their absorption in the gastrointestinal (GI) tract of man [1]. The largest part of the presently available information has been obtained indirectly, by using a pharmacokinetic treatment of plasma concentration- time profiles. When a drug can be administered to the same subjects intravenously and orally, it is possible to build up a model simulating the absorption profile [2]. Even if the intravenous administration is not permitted, special pharmacokinetic techniques allow such a model to be obtained [3,4]. Nevertheless, the indirect pharmacokinetic approach generally considers the absorption process as a whole, and it is unable to estimate the absorption rate at the various absorption sites of the GI tract.

The only way to obtain a complete and detailled picture of the absorption processes in man is to measure the disappearance of the drug from the various parts of the GI tract. This procedure has been used for a long time to study the absorption and digestion of nutrients, it has been progressively sophisticated and validated, and it is surprising that it has not yet been used to investigate the absorption of drugs, except on rare occasions. This paper will describe some variants of this technique as far as they can be applied to the problem of drug absorption in man, and give an example of the results they can provide.

The first studies on the physiology of digestion were based on a balance method, i.e. the comparison of the amount ingested and that recovered from the GI tract. A simple tube was used to collect the luminal fluid, but this did not permit precise measurements as only a fraction of the fluid passing at the sampling site was collected. In 1936, Abbott and Miller [5] proposed an improved procedure: a segment of the intestine was isolated between two inflatable balloons, so that the whole luminal content could be collected without dilution by the digestive secretions coming from the upper part of the GI tract. But this procedure was likely to disturb the intestinal motility and the blood supply to the mucosa. Hyden in 1956 [6] demonstrated that PEG 4000 is practically not absorbed in the intestine of man, and since this time it has been widely used as a non-absorbable marker in intubation studies. As early as 1957, Borgström et al. [7] studied the intestinal digestion and absorption of a liquid meal given with PEG 4000. In 1961, Schedl and Clifton [8], and Fordtran et al. [9] proposed simultaneously the intestinal perfusion technique with markers to evaluate intraluminal water movements. This type of experiment was validated by Jacobson et al. in 1963 [10]. Later on, the intubation techniques with non-absorbable markers were extensively applied to the study of the absorption of water, electrolytes, carbohydrates, lipids, biliary salts, vitamins, etc.… A more elaborate procedure was employed in 1971 by Bernier and Lebert [11] to investigate both the gastric emptying and the jejunal flow rate after the ingestion of a liquid meal. Two collection tubes were used, one in the stomach, the other in the duodenum, as well as two non-absorbable markers, one dissolved in the meal, the other perfused at a constant rate by a third tube in the duodenum, above the duodenal collection tube. This procedure was further described by Malagelada et al. [12], who applied it in extensive investigations on digestion processes.