Drug metabolism and metabolite transport in the small and large intestine: experiments with 1-naphthol and phenolphthalein by luminal and contraluminal administration in the isolated guinea pig mucosa

Abstract

The metabolism and metabolite transport of the monophenol 1-naphthol (I) and the diphenol phenolphthalein (II) have been studied in a symmetrical setup of the isolated jejunal and colonic mucosa from the guinea pig (Lauterbach 1977). In both tissues, the main metabolites of I were its sulphoconjugate and glucuronide, but the rate of metabolism, relative proportion of the metabolites and their distribution pattern varied with tissue and drug administration side in the following manner: By luminal administration (50 nmol/ml) in the jejunum, the metabolism was nearly complete within 45 min., more sulphate (1.5-3x) than glucuronide was formed, and both metabolites were predominantly transferred back to the lumen. By blood-side administration, the metabolism was less complete due to a significant decrease of the sulphated fraction. In consequence, more glucuronide (1.5-3x) than sulphate was formed. Moreover, the efflux pattern of the metabolites changed completely; the greater part of the glucuronide fraction now being conveyed to the blood side, whereas the sulphate tended to distribute in a 1:1 fashion on the lumen and blood side. The colonic mucosa behaved in a dissimilar way, since neither I metabolism nor metabolite efflux pattern in this tissue was influenced significantly by drug administration side. More sulphate (1.5-3x) than glucuronide was formed by both routes, and the metabolite distribution was similar to that observed by blood side administration in the jejunum. The changes described above were associated with changes in tissue accumulation of free I and metabolites; accumulation of I by luminal administration in jejunum was insignificant and that of the metabolites small. The main change caused by a higher concentration of I (130 nmol/ml) was a decrease in the sulphated fraction in the colon. II was metabolized at a slower rate than I, and a significant tissue accumulation of free II was observed in all instances. The monoglucuronide was the main metabolite. Only minor amounts of II monosulphate were formed, making its distribution pattern difficult to ascertain. The distribution of II monoglucuronide on the other hand was generally similar to that described for its I analogue.