Wallemacq P E, Verbeeck R K
Department of Clinical Chemistry, University Hospital St Luc, Catholic University of Louvain, Brussels, Belgium.
Clin Pharmacokinet. 2001;40(4):283-95. doi: 10.2165/00003088-200140040-00004.
Tacrolimus is a potent immunosuppressive agent used to prevent allograft rejection. The pharmacokinetics of tacrolimus have been studied in healthy volunteers and transplant recipients, mostly by using immunoassays to measure tacrolimus in plasma or blood. However, because of the cross-reactivity for certain tacrolimus metabolites of the antibodies used, these methods often lack specificity. This should be carefully taken into account when interpreting pharmacokinetic results for tacrolimus. In adult patients, tacrolimus is generally rapidly absorbed following oral administration (the time to reach maximum concentration is 1 to 2 hours), but in some patients absorption is slow or even delayed. Because of presystemic elimination, the oral bioavailability is low (around 20%) but may vary between 4 and 89%. Tacrolimus is highly bound to erythrocytes. Its binding to plasma proteins varies between 72 and 98% depending on the methodology used. Because of the extensive partitioning of tacrolimus into erythrocytes, its apparent volume of distribution (Vd) based on blood concentrations is much lower (1.0 to 1.5 L/kg) compared with values based on plasma concentrations (about 30 L/kg). Tacrolimus is metabolised by cytochrome P450 (CYP) 3A4 to at least 10 metabolites, some of which retain significant activity. Biliary excretion is the route of elimination of the tacrolimus metabolites. Systemic plasma clearance of tacrolimus is very high (0.6 to 5.4 L/h/kg), whereas blood clearance is much lower (0.03 to 0.09 L/h/kg). The terminal elimination half-life (t1/2beta) of tacrolimus is approximately 12 hours (with a range of 3.5 to 40.5 hours). Only limited information is available on the pharmacokinetics of tacrolimus in paediatric patients. The rate and extent of tacrolimus absorption after oral administration do not seem to be altered in paediatric patients. The Vd of tacrolimus based on blood concentrations in paediatric patients (2.6 L/kg) is approximately twice the adult value. Blood clearance of tacrolimus is also approximately twice as high in paediatric (0.14 L/h/kg) compared with adult (0.06 L/h/kg) patients. Consequently, t1/2beta does not appear modified in children, but oral doses need to be generally 2-fold higher than corresponding adult doses to reach similar tacrolimus blood concentrations. More pharmacokinetic studies in paediatric patients are, however, needed to rationalise the use of therapeutic drug monitoring for optimisation of tacrolimus therapy in this patient population.
他克莫司是一种强效免疫抑制剂，用于预防同种异体移植排斥反应。已在健康志愿者和移植受者中研究了他克莫司的药代动力学，主要是通过免疫测定法来测量血浆或血液中的他克莫司。然而，由于所用抗体对某些他克莫司代谢物存在交叉反应，这些方法往往缺乏特异性。在解释他克莫司的药代动力学结果时应仔细考虑这一点。在成年患者中，他克莫司口服给药后一般吸收迅速（达到最大浓度的时间为1至2小时），但在一些患者中吸收缓慢甚至延迟。由于首过消除，口服生物利用度较低（约20%），但可能在4%至89%之间变化。他克莫司与红细胞高度结合。其与血浆蛋白的结合率根据所用方法不同在72%至98%之间变化。由于他克莫司大量分布到红细胞中，基于血药浓度的表观分布容积（Vd）与基于血浆浓度的值（约30L/kg）相比要低得多（1.0至1.5L/kg）。他克莫司经细胞色素P450（CYP）3A4代谢为至少10种代谢物，其中一些仍保留显著活性。胆汁排泄是他克莫司代谢物的消除途径。他克莫司的全身血浆清除率非常高（0.6至5.4L/h/kg），而血液清除率则低得多（0.03至0.09L/h/kg）。他克莫司的终末消除半衰期（t1/2β）约为12小时（范围为3.5至40.5小时）。关于他克莫司在儿科患者中的药代动力学仅有有限的信息。儿科患者口服给药后他克莫司的吸收速率和程度似乎未改变。基于血药浓度的儿科患者他克莫司Vd（2.6L/kg）约为成人值的两倍。与成人患者（0.06L/h/kg）相比，儿科患者（0.14L/h/kg）他克莫司的血液清除率也约高两倍。因此，儿童的t1/2β似乎未改变，但为达到相似的他克莫司血药浓度，口服剂量通常需要比相应成人剂量高2倍。然而，需要在儿科患者中进行更多药代动力学研究，以合理使用治疗药物监测来优化该患者群体的他克莫司治疗。
