Review: first-pass metabolism by the gastrointestinal mucosa

Abstract

The bioavailability of orally administered drugs may be reduced due to presystemic elimination. The first-pass effect can occur in the gastrointestinal tract, the liver and lung. Although the liver is the main drug metabolizing organ in the body, the gut wall can play an important role in the first-pass metabolism of certain drugs. Both phase I (preconjugation) and phase II (conjugation) reactions have been described. However, while the oxidative metabolic capacity of the intestinal mucosa is considerably smaller than that of the liver, the activity of conjugation reactions in the gut may be close to that of the liver, and in some cases may exceed it. Sulphate conjugation is particularly important for steriod hormones such as ethinyloestradiol, and for the beta-adrenoceptor stimulants isoprenaline and isoetharine. Glucuronidation has been demonstrated to occur in man for morphine, paracetamol and oestrogens. Significant drug--drug interactions have been described involving drugs undergoing sulphate conjugation. The study of intestinal metabolism in vivo is difficult in man since direct methods (for example, hepatic portal vein catheterization) is justified in only a small number of patients. Therefore, much of our present understanding has been derived from various in-vitro studies involving intestinal sheets, mucosal biopsies, isolated enterocytes and microsomal preparations.