Laboratory of Pharmacology and Department of Anaesthesiology, University Hospital Centre of Caen, 14032, Caen Cédex, France.
Clin Drug Investig. 1996 Aug;12(2):67-79. doi: 10.2165/00044011-199612020-00002.
Ten patients with orthotopic liver transplants were investigated during routine therapeutic monitoring to study the relationship between the concentrations of cyclosporin and its metabolites in blood, bile and urine, and whether this information can provide early signs of severe hepatic disorders post-transplantation. Cyclosporin (Sandimmun®) was administered by continuous infusion at a constant rate of 5 mg/kg/day, modified to keep the blood cyclosporin concentration within the target range (400 to 500 μg/L). The concentrations of cyclosporin and combined cyclosporin-metabolites in blood, bile and urine were assayed daily during the 3 post-transplantation weeks that the patients spent in intensive care.All patients developed cholestatis and cytolysis during the first week. The severity of these liver transplant disorders increased in 5 patients and decreased in the other 5 in the second week. The pharmacokinetics of cyclosporin differed in the 2 groups: in patients without severe hepatic disorders, the blood metabolites/cyclosporin ratio (M/C) stabilised at 1.2 ± 0.4 in week 2 and at 0.8 ± 0.2 in week 3, bile cyclosporin/blood cyclosporin (bile C/blood C) fluctuated around 13.5 (13.5 ± 9.5 in week 2 and 13.5 ± 9.0 in week 3) and the bile metabolite/blood metabolite (bile M/blood M) ratio was very high and variable (131 ± 86 in week 2 and 159 ± 116 in week 3). Metabolites significantly accumulated in the blood of patients with severe hepatic disorders (M/C = 2.8 ± 0.6 in week 2 and 3.5 ± 1.0 in week 3); bile C/blood C (2.6 ± 2.1 in week 2 and 3.4 ± 1.1 in week 3) and bile M/blood M (11.9 ± 7.8 in week 2 and 12.5 ± 7.9 in week 3) significantly decreased and showed less interindividual variability.Blood cyclosporin is usually monitored to help optimise the dosage. However, if this was extended to include the monitoring of metabolites in the blood, and cyclosporin and metabolites in the bile, it could provide an early indication of severe hepatic disorders in patients with transplanted livers.
10 例原位肝移植患者在常规治疗监测期间接受了调查，以研究血液、胆汁和尿液中环孢素及其代谢物浓度之间的关系，以及这些信息是否能提供肝移植后严重肝障碍的早期迹象。环孢素（Sandimmun®）以 5mg/kg/天的恒定速度持续输注给药，调整剂量以保持血液中环孢素浓度在目标范围内（400 至 500μg/L）。在移植后 3 周的强化护理期间，每天检测血液、胆汁和尿液中环孢素和组合环孢素代谢物的浓度。所有患者在第一周均发生胆汁淤积和细胞溶解。这 5 例患者的肝移植障碍严重程度在第二周增加，另外 5 例患者的严重程度在第二周减轻。环孢素的药代动力学在两组患者中有所不同：在没有严重肝障碍的患者中，血液代谢物/环孢素（M/C）比值在第 2 周稳定在 1.2±0.4，在第 3 周稳定在 0.8±0.2，胆汁中环孢素/血液中环孢素（bile C/blood C）波动在 13.5 左右（第 2 周为 13.5±9.5，第 3 周为 13.5±9.0），胆汁代谢物/血液代谢物（bile M/blood M）比值非常高且变化较大（第 2 周为 131±86，第 3 周为 159±116）。在严重肝障碍患者的血液中，代谢物明显积聚（M/C=2.8±0.6，第 2 周和第 3 周为 3.5±1.0）；bile C/blood C（第 2 周为 2.6±2.1，第 3 周为 3.4±1.1）和 bile M/blood M（第 2 周为 11.9±7.8，第 3 周为 12.5±7.9）明显降低，个体间变异性降低。通常监测血液中环孢素以帮助优化剂量。然而，如果将其扩展到监测血液中的代谢物以及胆汁中的环孢素和代谢物，则可以为肝移植患者的严重肝障碍提供早期迹象。
