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

The influence of liver dysfunction on cyclosporine pharmacokinetics -A comparison between 70 per cent hepatectomy and complete bile duct ligation in dogs-

The influence of experimentally induced hepatic dysfunction on the pharmacokinetics of Cyclosporine A (CsA) was determined in dogs. The pharmacokinetics of oral (PO) and intravenous (IV) CsA were studied before and after 70 per cent hepatectomy or complete bile duct ligation (CBDL). Changes in liver function were monitored by serial measurements of serum bilirubin, and by the maximum removal rate (Rmax) and plasma disappearance rate (ICG-K) of indocyanine green (ICG). Concentrations of CsA in whole blood were measured by HPLC. Seventy per cent hepatectomy caused significant liver dysfunction: the ICG-Rmax decreased by 47.7±7.1 per cent (mean±SD) and the ICG-K decreased by 61.3±9.7 per cent during the first week after hepatectomy. At the same time, the systemic clearance (CLs) of IV-CsA decreased by 43.9±8.2 per cent, the area under the concentration curve (AUC) of IV-CsA increased by 35.4±20.8 per cent and the bioavailability of CsA decreased by 26.4±14.8 per cent. CBDL also induced significant liver dysfunction: the ICG-Rmax decreased by 39.1±12.8 per cent and the ICG-K decreased by 65.6±3.6 per cent in the second week after the operation. During the same period, the AUC of PO-CsA decreased by 69.9±10.7 per cent and the bioavailability of CsA also decreased markedly by 73.9±15.6 per cent. These data indicate that hepatic impairment significantly influences the pharmacokinetics of CsA, not only by the changes in intestinal absorption, but also by those in hepatic, metabolism. Dose adjustment is therefore necessary in the presence of hepatic dysfunction in order to maintain an adequate blood concentration of CsA without causing side effects. © 1989 The Japan Surgical Society

In-vitro Interaction of a Novel Immunosuppressant, FK 506, and Antacids

Abstract-The effect of selected antacids on the amount ofFK 506 in solution in simulated gastric juice has been studied. FK 506 (2·5 mg) was incubated in 100 mL simulated gastric fluid (SGF) with the equivalent of 500 mg of various antacids. The addition of Mylanta and Turns resulted in 14 and 30'1., loss of FK 506, respectively, in 24 h; 98% loss was observed in 12 h in the presence of Mag-Ox; 100'Yo loss was observed in the presence of magnesium oxide powderin 2 h. The loss ofFK 506 from these solutions appears to be due to a pH mediated degradation of FK 506. The addition of aluminium hydroxide gel USP (Roxane) to the FK 506 solution resulted in a 35°;;, loss within 2 min but no further loss was noted for 24 h. indicative of adsorption ofFK 506. These results suggest that until additional in-vivo studies are carried out. it is prudent not to dose FK 506 and antacids at the same time to avoid potential interactions