Pharmacokinetics of tacrolimus during pregnancy.
Pharmacokinetics of tacrolimus during pregnancy.
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他克莫司在怀孕期间的药代动力学。
DOI：
10.1097/ftd.0b013e3182708edf
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发表时间：
2012-12
影响因子：
2.5
通讯作者：
Hebert MF
中科院分区：
文献类型：
--
作者：
Zheng S;Easterling TR;Umans JG;Miodovnik M;Calamia JC;Thummel KE;Shen DD;Davis CL;Hebert MF
尽管越来越多的孕妇服用他克莫司用于免疫抑制，但关于妊娠期间他克莫司药代动力学的信息仅限于病例报告。在一个稳定的给药间隔内，从妊娠早期到晚期（n = 10）和产后（n = 5）接受口服他克莫司治疗的妇女收集血液、血浆和尿液样本。采用经验证的LC/MS/MS方法检测血液和血浆中他克莫司的总浓度和未结合浓度以及代谢物浓度。采用混合效应线性模型进行全胎龄比较，并以产后组为参照组。基于全血他克莫司浓度的平均口服清除率（CL/F）在妊娠中后期比产后高39%（47.4±12.6 vs 34.2±14.8 L/h, P < 0.03）。妊娠期血浆他克莫司游离分数（fP）升高91%，血液他克莫司游离分数（fB）升高100% （P = 0.0007和0.002）。fP升高与血清白蛋白浓度呈负相关（r = - 0.7, P = 0.003），妊娠期血清白蛋白浓度下降27%。妊娠相关的fP和fB变化对他克莫司全血CL/F升高有显著影响（r2分别为0.36和0.47,P < 0.01）。此外，他克莫司全血CL/F与红细胞压积和红细胞计数呈负相关，表明他克莫司与红细胞的结合限制了其代谢的可用性。治疗医生将妊娠期研究参与者的他克莫司剂量平均增加45%，以维持他克莫司全血谷浓度在治疗范围内。这导致妊娠期间未结合的他克莫司谷浓度和未结合的AUC分别显著增加112%和173% （P分别= 0.02和0.03）。他克莫司的药代动力学在妊娠期间发生改变。在妊娠期间调整剂量以维持全血他克莫司浓度在常规治疗范围内会增加循环游离药物浓度，这可能会影响临床结果。
Information on the pharmacokinetics of tacrolimus during pregnancy is limited to case reports despite the increasing number of pregnant women being prescribed tacrolimus for immunosuppression. Blood, plasma and urine samples were collected over one steady-state dosing interval from women treated with oral tacrolimus during early to late pregnancy (n = 10) and postpartum (n = 5). Total and unbound tacrolimus as well as metabolite concentrations in blood and plasma were assayed by a validated LC/MS/MS method. A mixed effect linear model was used for comparison across gestational age and using postpartum as the reference group. The mean oral clearance (CL/F) based on whole blood tacrolimus concentration was 39% higher during mid- and late-pregnancy compared to postpartum (47.4 ± 12.6 vs. 34.2 ± 14.8 L/h, P < 0.03). Tacrolimus free fraction increased by 91% in plasma (fP) and by 100% in blood (fB) during pregnancy (P = 0.0007 and 0.002, respectively). Increased fP was inversely associated with serum albumin concentration (r = − 0.7, P = 0.003), which decreased by 27% during pregnancy. Pregnancy related changes in fP and fB contributed significantly to the observed gestational increase in tacrolimus whole blood CL/F (r2 = 0.36 and 0.47 respectively, P < 0.01). In addition, tacrolimus whole blood CL/F was inversely correlated with both hematocrit and red blood cell counts, suggesting that binding of tacrolimus to erythrocytes restricts its availability for metabolism. Treating physicians increased tacrolimus dosages in study participants during pregnancy by an average of 45% in order to maintain tacrolimus whole blood trough concentrations in the therapeutic range. This led to striking increases in unbound tacrolimus trough concentrations and unbound AUC, by 112% and 173%, respectively during pregnancy (P = 0.02 and 0.03, respectively). Tacrolimus pharmacokinetics are altered during pregnancy. Dose adjustment to maintain whole blood tacrolimus concentration in the usual therapeutic range during pregnancy increases circulating free drug concentrations, which may impact clinical outcomes.