Sensitivity of activated human lymphocytes to cyclosporine and its metabolites

Alloreactive T cells generated as clones from mixed lymphocyte cultures, or propagated from heart or liver transplant biopsies, were tested for secondary proliferation measured in the primed lymphocyte test in the presence of Cyclosporine A and metabolites fractionated from human bile. Significant differences were observed in Cyclosporine A sensitivity between various cell cultures ranging as high as 100-fold. The liver is the primary site of Cyclosporine A metabolism, which yields a number of hydroxylated and N-dimethylated derivatives that are eventually secreted into the bile. Bile was collected from adult liver transplant patients on Cyclosporine A therapy and following extraction with diethyl ether, separated by high pressure liquid chromatography. Thirteen fractions were tested for their effect on lymphocyte proliferation in concanavalin A activation, mixed lymphocyte cultures and primed lymphocyte test assays. The strongest immunosuppressive effect was found with fraction 8, which contained metabolite M17, which has a single hydroxylation in position 1. Only three other fractions 9, 10, and 13, which contained metabolites M1, M18, and M21, respectively, exhibited immunosuppressive activity, albeit much lower than that of Cyclosporine A. Differences in Cyclosporine A sensitivity among alloreactive T cells followed similar patterns with Cyclosporius A metabolites. Thus, the assessment of the Cyclosporine A effect must consider differences in drug sensitivity of lymphocytes involved in transplant immunity and the generation of metabolites with immunosuppressive activity. © 1988

Rapid growth of an intact human liver transplanted into a recipient larger than the donor

Two individuals undergoing orthotopic hepatic transplantation received livers from donors who were on average 10 kg smaller than themselves based on recipient ideal body weight. As a result, the donor livers in these 2 cases were 29%-59% smaller than would be expected had the donor liver and recipient been matched ideally. The liver grafts in the recipients steadily increased in size, as determined by serial computed tomography scanning, to achieve new volumes consistent with those that would have been expected in a normal individual of the recipient's size, sex, and age. Fasting plasma levels of amino acids, glucagon, insulin, and standard liver injury tests were monitored to determine which measure best reflected the changes observed in the size of the grafts over time. No relationship between the changes observed in any of these parameters and hepatic growth was apparent. In both cases, the liver increased in volume at a rate of ~70 ml/day. These data demonstrate that a small-for-size liver transplanted into a larger recipient increases in size at a rate of ~70 ml/day until it achieves a liver volume consistent with that expected given the recipient's size, age, and sex. © 1987

Effect of bile on cyclosporine absorption in dogs

Oral absorption of cyclosporine was studied in dogs with and without bile diversion. Blood and bile cyclosporine concentrations were determined by a high pressure liquid chromatographic method. The absorption of cyclosporine was signficantly impaired (p < 0.05) in dogs with bile diversion. Bile and bile salts appear to be essential for the absorption of cyclosporine