血细胞比容对成年活体供肝移植受者他克莫司药代动力学的影响。

Effect of hematocrit on pharmacokinetics of tacrolimus in adult living donor liver transplant recipients.

作者信息

Minematsu T, Sugiyama E, Kusama M, Hori S, Yamada Y, Ohtani H, Sawada Y, Sato H, Takayama T, Sugawara Y, Makuuchi M, Iga T

机构信息

Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

出版信息

Transplant Proc. 2004 Jun;36(5):1506-11. doi: 10.1016/j.transproceed.2004.04.097.

DOI:10.1016/j.transproceed.2004.04.097

PMID:15251372

Abstract

OBJECTIVE

Plasma drug concentrations are generally considered to reflect efficacy and pharmacokinetics more directly than those in whole blood. However, whole blood has been selected as the matrix to monitor concentrations of tacrolimus (FK506), because it is difficult to accurately measure plasma FK506 concentrations. Because FK506 highly and saturably binds in blood cells, a change in hematocrit value (Hct) may affect FK506 pharmacokinetics. Therefore, we investigated effects of Hct on FK506 pharmacokinetics.

METHODS

First, we analyzed data on FK506 distribution among human blood cells in vitro. Briefly, we employed an equation, which describes saturable binding of FK506 to blood cells, and simulated plasma FK506 concentrations and clearances using the above equation with respect to a variable Hct. Subsequently, we retrospectively analyzed dosages and whole blood FK506 concentrations to predict plasma FK506 concentrations in living donor transplant recipients.

RESULTS

In the simulation study, the Hct changed plasma FK506 concentrations and clearances based in whole blood. In living donor liver transplant recipients, whole blood FK506 concentrations were maintained within a therapeutic range, while the Hct varied after transplantation. The correlation of Hct with the ratio of dose/trough concentrations of FK506 (D/C) in plasma (D/Cp) (R = -0.23, n = 343) was weaker than that for D/C in whole blood (D/CWB) (R = -0.53, n = 343).

CONCLUSION

Hct may be an important factor affecting the pharmacokinetics of FK506 in living donor liver transplantation recipients. It may be necessary to take Hct into consideration in the FK506 dosing regimen, especially when the Hct is low.

摘要

目的

血浆药物浓度通常被认为比全血药物浓度更能直接反映疗效和药代动力学。然而，由于难以准确测量血浆中他克莫司（FK506）的浓度，全血已被选作监测他克莫司浓度的基质。由于FK506在血细胞中高度且可饱和结合，血细胞比容值（Hct）的变化可能会影响FK506的药代动力学。因此，我们研究了Hct对FK506药代动力学的影响。

方法

首先，我们分析了FK506在人血细胞中的体外分布数据。简而言之，我们采用了一个描述FK506与血细胞可饱和结合的方程，并使用上述方程针对可变的Hct模拟血浆FK506浓度和清除率。随后，我们回顾性分析了活体供体移植受者的剂量和全血FK506浓度，以预测血浆FK506浓度。

结果

在模拟研究中，Hct改变了基于全血的血浆FK506浓度和清除率。在活体供体肝移植受者中，全血FK506浓度维持在治疗范围内，而移植后Hct有所变化。Hct与血浆中FK506剂量/谷浓度比（D/C）（D/Cp）的相关性（R = -0.23，n = 343）弱于全血中D/C（D/CWB）的相关性（R = -0.53，n = 343）。