Department of Pharmaceutics, University of Washington, Seattle, WA, USA.
Br J Clin Pharmacol. 2013 Dec;76(6):988-96. doi: 10.1111/bcp.12122.
AIM(S): The current investigation aims to provide new insights into fetal exposure to tacrolimus in utero by evaluating maternal and umbilical cord blood (venous and arterial), plasma and unbound concentrations at delivery. This study also presents a case report of tacrolimus excretion via breast milk.
Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject.
Mean (±SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 ± 1.8 ng ml(-1)) were 71 ± 18% (range 45-99%) of maternal concentrations (9.0 ± 3.4 ng ml(-1)). The mean umbilical cord venous plasma (0.09 ± 0.04 ng ml(-1)) and unbound drug concentrations (0.003 ± 0.001 ng ml(-1)) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 ± 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose.
Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P-gp function, greater red blood cell partitioning and higher haematocrit levels in venous cord blood. The neonatal drug exposure to tacrolimus via breast milk is very low and likely does not represent a health risk to the breastfeeding infant.
本研究旨在通过评估产妇和脐血（静脉和动脉）、分娩时血浆和未结合浓度，为胎儿在宫内接触他克莫司提供新的见解。本研究还报告了一例他克莫司通过母乳排泄的病例。
从 8 名实体器官移植受者分娩时获得产妇和脐血（静脉和动脉）样本，以测量血液和血浆中他克莫司和代谢物结合和未结合浓度。在 1 名受试者中评估了母乳中他克莫司的药代动力学。
分娩时脐静脉血中他克莫司的平均（±SD）浓度（6.6±1.8ng/ml）为产妇浓度（9.0±3.4ng/ml）的 71±18%（范围 45-99%）。脐静脉血浆的平均浓度（0.09±0.04ng/ml）和未结合药物浓度（0.003±0.001ng/ml）约为母体浓度的五分之一。动脉脐血中他克莫司的浓度为脐静脉浓度的 100±12%。此外，婴儿通过母乳接触他克莫司的量不到母亲体重调整剂量的 0.3%。
母体和脐血他克莫司浓度的差异部分可归因于胎盘 P-糖蛋白功能、红细胞更多的分配和静脉脐血更高的血细胞比容水平。新生儿通过母乳接触他克莫司的药物暴露量非常低，不太可能对母乳喂养的婴儿造成健康风险。
