Wingard J R, Nash R A, Ratanatharathorn V, Fay J W, Klein J L, Przepiorka D, Maher R M, Devine S M, Boswell G, Bekersky I, Fitzsimmons W
University of Florida College of Medicine, Department of Medicine, Gainesville 32610-0277, USA.
Bone Marrow Transplant. 1997 Jul;20(1):49-51. doi: 10.1038/sj.bmt.1700839.
Tacrolimus (FK506) is a macrolide lactone effective in the control of graft-versus-host disease (GVHD). An interaction between high-dose methotrexate and a macrolide antibiotic (pristinamycin) leading to prolonged methotrexate exposure has been described. Because a randomized prospective trial comparing tacrolimus with cyclosporine (both in combination with methotrexate) following allogeneic BMT showed the tacrolimus plus methotrexate regimen to be more effective in prevention of GVHD, we assessed methotrexate pharmacokinetics in a subgroup of the participants of this trial to evaluate the possibility that an interaction of FK506 and methotrexate was the explanation for the clinical findings. Mean and median methotrexate levels at various time-points after the day 1 and 6 methotrexate doses were comparable in the tacrolimus and cyclosporine cohorts and were elevated in only three of 70 study patients. Area under the curve (AUC) concentrations were also similar after the day 1 and 6 methotrexate doses. Thus, no significant interaction between tacrolimus and methotrexate is apparent and the differences in efficacy between tacrolimus and cyclosporine are unlikely to be attributable to pharmacologic interactions with methotrexate.
他克莫司（FK506）是一种大环内酯类内酯，对控制移植物抗宿主病（GVHD）有效。曾有报道称，高剂量甲氨蝶呤与一种大环内酯类抗生素（ pristinamycin）之间存在相互作用，导致甲氨蝶呤暴露时间延长。由于一项比较他克莫司与环孢素（均与甲氨蝶呤联合使用）在异基因骨髓移植后的随机前瞻性试验表明，他克莫司加甲氨蝶呤方案在预防GVHD方面更有效，我们评估了该试验部分参与者中甲氨蝶呤的药代动力学，以评估FK506与甲氨蝶呤相互作用是否能解释临床结果。在他克莫司和环孢素组中，第1天和第6天给予甲氨蝶呤剂量后不同时间点的甲氨蝶呤平均水平和中位数水平相当，且70例研究患者中只有3例升高。第1天和第6天给予甲氨蝶呤剂量后的曲线下面积（AUC）浓度也相似。因此，他克莫司与甲氨蝶呤之间没有明显的显著相互作用，他克莫司与环孢素之间疗效的差异不太可能归因于与甲氨蝶呤的药物相互作用。
