THE ISOLATED GUT PREPARATION: AN UNAMBIGUOUS METHOD OF SCREENING COMPOUNDS FOR GUT METABOLISM

Abstract

In the design of effective and safe drugs for oral administration several ‘biological aspects’ are crucial. These include the extent to which the parent drug is absorbed from the gut and the nature and extent of metabolism either in the gut contents and/or during transport across the gut wall into blood. The most unambiguous method of measuring both the absorption of drugs from the gut lumen and, in particular, the activation or deactivation of drugs by the gut, is using the isolated vascular perfused intestine. In the basic model, a segment of intestine extending from the pyloric sphincter to the caecum is isolated and perfused via the mesenteric artery with diluted oxygenated heparinised blood at 37°C and 60-80 mmHg pressure. Venous blood from the portal vein is re-oxygenated and returned to the blood reservoir. Bile is infused into the gut lumen via a cannula inserted into the bile duct. For absorption/metabolism studies the drugs are administered directly into the gut lumen. However, when the contribution of the gut to the metabolism of blood-borne drugs is required, the compounds are added directly into the blood perfusate. After dosing blood samples are removed, at time intervals, up to 4 hours for quantitative and qualitative analysis. Alternatively, all the effluent perfusate from the portal vein may be collected for first pass studies. This presentation will deal with the transport and metabolism in the gut of a variety of compounds of disparate structures including low molecular weight, organics, steroids and peptides.