The clinical effectiveness of cyclosporine is limited by changes in resorption and metabolism of cyclosporine and by possible drug interactions. This study examined the influence of five gastrointestinal agents on duration and resorption of cyclosporine and dosage/level relations: cimetidine, famotidine, pirenzepine, aluminum hydroxide, and omeprazole. These gastrointestinal agents were studied in 64 rat experiments, in which the impact of each single drug and of drug combinations on cyclosporine resorption and metabolism was tested. A standardized dosage of cyclosporine was given orally, and the duration was calculated for the maximum whole blood level of cyclosporine to be achieved; the dosage/level quotient was calculated. Cimetidine, famotidine, pirenzepine, and combination treatment prolonged duration of cyclosporine resorption. Furthermore, cimetidine, famotidine, and omeprazole lowered the dosage/level quotient, thus leading to higher cyclosporine levels with the same dosage; pirenzepine increased the dosage/level quotient. For clinical comparison, 163 heart transplant patients who had received standard triple-drug immunosuppressive therapy were analyzed. The time interval until a therapeutic cyclosporine level was achieved and the dosage/level quotient were once again calculated. Similar to the results in the animal experiments, cimetidine and famotidine significantly delayed the resorption of cyclosporine; cimetidine, famotidine, and omeprazole lowered the cyclosporine dosage/level quotient, thus leading to higher cyclosporine levels with the same dosage. Aluminum hydroxide did not lead to any changes in the resorption or metabolism of cyclosporine. Most examined gastrointestinal agents, and particularly H2-blocking drugs, led to significant prolongation of cyclosporine resorption and cyclosporine level alterations. The initial prolongation of cyclosporine resorption was successfully avoided by intravenous administration of cyclosporine for the first 4 postoperative days in 40 consecutive patients.