FIRST-PASS EFFECT - SIGNIFICANCE OF THE INTESTINE FOR ABSORPTION AND METABOLISM

The occurrence of low systemic availability due to significant metabol ism or poor absorption of orally administered drugs has been well reco gnized. Three rate controlling factors affecting the oral absorption:u nstirred water layer, membrane limitation, or flow limitation, have be en identified. These are much affected by the physicochemical properti es of the drug: pK(A), water/lipid solubility, structural mimicry to e ndogenous substrates for transport proteins, and the physiology of the GI tract. Drug metabolizing enzymes are found to be present in the in testine, albeit the content is lower than that found in liver. The pre sence of pre-absorptive versus post-absorptive intestinal metabolism i s presently discussed in experimental sets of data with luminal and sy stemic administration of the drugs in the vascularly perfused rat smal l intestine preparation. The effect of the anterior anatomical placeme nt of the intestine and its contribution to metabolism, in relation to that for the liver, has been examined in our laboratory by the perfus ed intestine-liver preparation. The effect of concentration and flow h ave been studied and general principles governing drug absorption and metabolism in the intestine and the subsequent effects on the liver ha ve been discussed.