在他克莫司维持治疗期间评估肌苷-5'-单磷酸脱氢酶的活性。

Evaluation of inosin-5'-monophosphate dehydrogenase activity during maintenance therapy with tacrolimus.

机构信息

Department of Clinical Pharmacy, School of Pharmacy, Shujitsu University, Okayama, Japan.

出版信息

J Clin Pharm Ther. 2010 Feb;35(1):79-85. doi: 10.1111/j.1365-2710.2009.01072.x.

DOI:10.1111/j.1365-2710.2009.01072.x

PMID:20175815

Abstract

OBJECTIVES

The aim of this study was to identify a target range for inosin-5'-monophosphate dehydrogenase (IMPDH) activity in maintenance therapy with tacrolimus (TCL), and to apply the measurement of IMPDH activity to the therapeutic drug monitoring for mycophenolate mofetil (MMF).

METHODS

Eleven patients with renal transplants and 10 healthy volunteers were investigated. All patients were treated with a combination of TCL, steroid and MMF for 2 months after transplantation, and were in stable and good condition. IMPDH activity was determined indirectly by measuring xanthosine 5'-monophophate in cell lysates supplemented with IMP and beta-nicotine adenine dinucleotide using an high-performance liquid chromatography (HPLC) method.

RESULTS

The within-run reproducibility of the assay was excellent, with relative standard deviation (RSD) values of 0.41-4.08%. The mean differences between the spiked concentrations of xanthosine 5'-monophophate and their real values (mean relative errors; MREs) were within a range of 2.66-8.89%, showing good accuracy. The interday RSD values were 1.51-6.12% and MREs ranged from 2.10% to 8.89%. Cell lysates showed a 5-6 nmol/L IC(50) mycophenolic acid (MPA) concentration. TCL, cyclosporine and prednisolone did not affect IMPDH activity. The peak MPA concentration was achieved at 1 h after dosing. IMPDH activity decreased to 75% and 67% at 1 and 2 h after dosing respectively. Therefore, the inhibition rates of MPA against IMPDH activity may be adequate at 25-40% in TCL maintenance therapy.

CONCLUSION

Inosin-5'-monophosphate dehydrogenase activity in cell lysates could be reliably determined by HPLC. A 25-40% inhibition of IMPDH activity may be an appropriate range for preventing rejection with MPF but this requires further validation using larger studies with harder outcomes such as rejection episodes.

摘要

目的

本研究旨在确定他克莫司（TAC）维持治疗中肌苷-5′-单磷酸脱氢酶（IMPDH）活性的靶标范围，并将 IMPDH 活性测量应用于霉酚酸酯（MPA）的治疗药物监测。

方法

研究了 11 例肾移植患者和 10 名健康志愿者。所有患者在移植后 2 个月内接受 TAC、类固醇和 MPA 联合治疗，且状态稳定、情况良好。通过在细胞裂解物中补充肌苷和 β-烟酰胺腺嘌呤二核苷酸，使用高效液相色谱（HPLC）法间接测定黄嘌呤 5′-单磷酸的量，从而测定 IMPDH 活性。

结果

该测定法的日内精密度良好，相对标准偏差（RSD）值为 0.41-4.08%。黄嘌呤 5′-单磷酸的加入浓度与其实际值之间的平均差异（平均相对误差；MRE）在 2.66-8.89%的范围内，表明准确度良好。日间 RSD 值为 1.51-6.12%，MRE 范围为 2.10%-8.89%。细胞裂解物中 5-6 nmol/L 的霉酚酸（MPA）浓度时，IC50 可抑制 IMPDH 活性。TAC、环孢素和泼尼松龙不影响 IMPDH 活性。MPA 的峰值浓度在给药后 1 小时达到。给药后 1 和 2 小时，IMPDH 活性分别下降至 75%和 67%。因此，TAC 维持治疗中，MPA 对 IMPDH 活性的抑制率可能在 25-40%之间是合适的。