Circumstantial evidence for first-pass metabolism across the gastrointestinal mucosa includes reduced bioavailability after oral administration, despite complete or good absorption. There may also be route-dependent variation in the pattern of metabolism with the latter occurring to a greater extent after oral administration than after parenteral injection. However, direct proof that first-pass metabolism takes place across the gastrointestinal mucosa relies upon cannulation of either the portal or mesenteric venous tree. Such studies are not possible in most patients because of the potential hazards involved and the attendant ethical considerations. Additional information has come from the study of enzyme activity in biopsies of intestinal mucosa and experiments performed on isolated loops of intestine in various animal species. Although the former have identified the fact that enzyme activity may vary along the length of the intestine and the latter have provided quantitative information on what can occur in vivo, these data cannot be extrapolated to intact man. Both phase I (preconjugation) and phase II (conjugation) reactions have been described. However, except for oxidative deamination, e.g. tyramine and hydrolysis of esters such as pivampicillin and aspirin, phase I reactions appear to be quantitatively unimportant. In contrast, synthetic reactions are much more active. Sulphate conjugation, in particular, is important for the beta-adrenoceptor stimulants isoprenaline (isoproterenol), isoetharine and rimiterol, as well as for steroid hormones. Glucuronidation has also been demonstrated to occur in man for a small number of drugs. N-Acetylation is an important pathway and, as in the liver, there is evidence of polymorphism. Metabolism of hydralazine, isoniazid, p-aminosalicylic acid as well as certain sulphonamides by intestinal N-acetyl transferase has been demonstrated, but in all probability affects other drugs as well. Little is known concerning the physiological factors which alter the activity of the gastrointestinal drug-metabolising enzymes. However, significant drug-drug interactions have been demonstrated to occur at this site-particularly for drugs which undergo sulphate conjugation.