Udomkarnjananun Suwasin, Eiamsitrakoon Thanee, de Winter Brenda C M, van Gelder Teun, Hesselink Dennis A
Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
Excellence Center for Organ Transplantation (ECOT), King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
Br J Clin Pharmacol. 2025 Jun;91(6):1530-1541. doi: 10.1111/bcp.15946. Epub 2023 Nov 22.
The measurement of whole blood (WB) concentrations has been the primary method for therapeutic drug monitoring of tacrolimus since its introduction in the field of organ transplantation. However, >99% of tacrolimus measured in WB is bound to erythrocytes and plasma proteins, which are the pharmacologically inactive fractions. The pharmacologically active fractions, the free (or unbound) tacrolimus in plasma and the intracellular tacrolimus, make up 1% or less of the WB concentration. The mechanism of action of tacrolimus is to inhibit the enzyme calcineurin within T lymphocytes and, therefore, measuring the intralymphocytic tacrolimus concentration may better reflect its pharmacodynamic effects and better correlate with clinical outcomes. However, studies on intracellular tacrolimus concentrations have shown conflicting results. In this review, we argue that we need to overcome the analytical limitations of current assays for the measurement of intracellular tacrolimus before moving this technique into the clinical setting. The validity and standardization of the cell isolation process before the measurement of the intracellular tacrolimus concentration is as important as the measurement itself but has received little attention in our view. Recent evidence suggests that the addition of an inhibitor of P-glycoprotein, an efflux transporter expressed on lymphocytes, prevents the expulsion of tacrolimus during the cell isolation process. Refining the technique for the intracellular tacrolimus concentration measurement should be the focus followed by clinical evaluation of its association with rejection risk.
自他克莫司引入器官移植领域以来，全血（WB）浓度测定一直是其治疗药物监测的主要方法。然而，在全血中测得的他克莫司>99%与红细胞和血浆蛋白结合，这些都是药理惰性部分。药理活性部分，即血浆中的游离（或未结合）他克莫司和细胞内他克莫司，占全血浓度的1%或更少。他克莫司的作用机制是抑制T淋巴细胞内的钙调神经磷酸酶，因此，测量淋巴细胞内他克莫司浓度可能更好地反映其药效学效应，并与临床结果有更好的相关性。然而，关于细胞内他克莫司浓度的研究结果相互矛盾。在本综述中，我们认为在将该技术应用于临床之前，我们需要克服当前检测细胞内他克莫司方法的分析局限性。在测量细胞内他克莫司浓度之前，细胞分离过程的有效性和标准化与测量本身同样重要，但在我们看来，这一点很少受到关注。最近的证据表明，添加一种P-糖蛋白抑制剂（一种在淋巴细胞上表达的外排转运蛋白）可防止在细胞分离过程中他克莫司被排出。完善细胞内他克莫司浓度测量技术应是重点，随后应对其与排斥风险的相关性进行临床评估。
