CYCLOSPORINE METABOLISM BY THE GASTROINTESTINAL MUCOSA

The intestinal mucosal metabolism of the immunosuppressant cyclosporin (CsA) has been studied in vitro using the Ussing chamber technique. Histologically normal colon was obtained from six patients undergoing resections. The mucosal sheets were mounted between two perspex chambers. Three hours after addition of [H-3]-CsA (0.2-mu-Ci; 10-mu-M) to the mucosal chamber, more than 90% of the radioactivity was present in that chamber. Metabolite analysis, by high performance liquid chromatography, indicated that 77.6 +/- 9.2% (mean +/- s.d.) of the drug present was CsA, 9.9 +/- 4.4% and 8.7 +/- 4.7% were the oxidative metabolites M17 and M21 respectively (metabolites identified by co-chromatography with authentic standards). Total metabolite production in tissues from the six individuals was variable (10.1-30.6% at 3 h) and increased over the time period of the study. A different pattern of metabolism was obtained from a single sample of gastric mucosa. More than 20% of CsA was metabolised although neither M17 nor M21 were detected. The results of this study suggest that the gut wall is involved in the first pass metabolism of CsA in vivo and that this could be a contributory factor to the poor systemic availability of CsA seen in some patients.