| 91 | 0 | 130 |
| 下载次数 | 被引频次 | 阅读次数 |
目的 研究肾移植患者外周血单个核细胞(PBMC)内霉酚酸(MPA)暴露量与药效指标次黄嘌呤单核苷酸脱氢酶(IMPDH)活性的相关性。方法 共纳入肾移植患者48例。根据MPA制剂的不同，将肾移植患者分成吗替麦考酚酯(MMF)组和麦考酚钠肠溶片(EC-MPS)组，各24例。于服用MMF或EC-MPS 2周后采集服药前(0 h)及服药后0.5、1.0、1.5、2.0、4.0、6.0、8.0、10.0、12.0 h血标本，采用液相色谱串联质谱法(LC-MS/MS)测定血浆中及PBMC内MPA浓度和黄苷酸(XMP)浓度(用于计算IMPDH活性)。采用Pearson法分析PBMC内MPA药动学参数(主要是与暴露量相关的C0、Cmax和AUC0-12h)与在血浆中的相关性，以及血浆中和PBMC内MPA浓度与IMPDH活性的相关性。结果 肾移植患者在服用MMF或EC-MPS后，PBMC内的MPA达峰时间与血浆中的一致。MMF组患者PBMC内的Cmax、C0、AUC0-12h与血浆中显著相关，相关系数(r)依次为0.538(P<0.01)、0.503(P<0.05)和0.472(P<0.05);EC-MPS组患者PBMC内的Cmax、C0、AUC0-12h与血浆中的r依次为0.147(P=0.494)、0.315(P=0.143)和0.431(P=0.065)。肾移植患者用药后随着MPA浓度增加，IMPDH活性下降，两者呈反比关系，在PBMC内趋势更加明显。结论 PBMC内MPA暴露量与血浆中存在一定相关性，且PBMC内MPA浓度更能直接地反映MPA对IMPDH活性的抑制作用，可作为MPA治疗药物监测的补充指标。
Abstract：AIM To study the pharmacokinetics of mycophenolic acid(MPA) in peripheral blood mononuclear cell(PBMC), and the correlation with inosine-5'-monophosphate dehydrogenase(IMPDH) activity in renal transplantation patients. METHODS A total of 48 renal transplant patients were included and divided into mycophenolate mofetil(MMF) group and enteric-coated mycophenolate sodium tablets(EC-MPS) group according to different MPA formulation types, with 24 patients in each group. Plasma samples were collected at baseline(0 h) and 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 12.0 hours after the administration of MMF or EC-MPS over 2 weeks from renal transplant patients. MPA concentration and xanthosine monophosphate(XMP) concentration(for calculation of IMPDH activity) in plasma and PBMC were measured by liquid chromatography-tandem mass spectrometry(LC-MS/MS). Pearson method was used to analyze the correlation between pharmacokinetic parameters of MPA in PBMC(mainly C0, Cmax and AUC0-12h related to exposure) and plasma, as well as the correlation between IMPDH activity and MPA concentration in plasma and PBMC. RESULTS For renal transplant recipients administered MMF or EC-MPS, the time to peak concentration of MPA in PBMC was consistent with that in plasma. There were statistically significant positive correlations between plasma and PBMC for Cmax(r = 0.538, P < 0.01), C0(r = 0.503, P < 0.05), and AUC0-12h(r = 0.472, P < 0.05) in patients taking MMF. The correlation coefficients for patients receiving EC-MPS were as follows: r = 0.147(P = 0.494) for Cmax, r = 0.315(P = 0.143) for C0, and r = 0.431(P = 0.065) for AUC0-12h. The activity of IMPDH decreased in an inverse relationship with increasing MPA concentrations in transplanted patients following drug administration, and the trend was more remarkable in PBMC. CONCLUSION A correlation between MPA exposure levels in PBMC and those in plasma has been observed. The MPA concentration in PBMC has been shown to reflect the inhibitory effect of MPA on IMPDH activity directly. Consequently, the MPA concentration in PBMC can be utilized as a complement to the TDM.
[1] ALLISON A C, KOWALSKI W J, MULLER C D, et al.Mechanisms of action of mycophenolic acid[J]. Ann N Y Acad Sci, 1993, 696:63.
[2] AIYEGBUSI O, MCGREGOR E, MCMANUS S K, et al.Immunosuppression therapy in kidney transplantation[J]. Urol Clin North Am, 2022, 49(2):345.
[3] JIAO Z, ZHONG J Y, ZHANG M, et al. Total and free mycophenolic acid and its 7-O-glucuronide metabolite in Chinese adult renal transplant patients:pharmacokinetics and application of limited sampling strategies[J]. Eur J Clin Pharmacol, 2007,63(1):27.
[4] BULLINGHAM R E, NICHOLLS A J, KAMM B R. Clinical pharmacokinetics of mycophenolate mofeti l[J]. Clin Pharmacokinet, 1998, 34(6):429.
[5] VAN GELDER T, SILVA H T, DE FIJTER J W, et al. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients:the fixed-dose concentration-controlled trial[J].Transplantation, 2008, 86(8):1043.
[6] COOPER M, SALVADORI M, BUDDE K, et al. Enteric-coated mycophenolate sodium immunosuppression in renal transplant patients:efficacy and dosing[J]. Transplant Rev(Orlando),2012, 26(4):233.
[7] ETTENGER R, BARTOSH S, CHOI L, et al. Pharmacokinetics of enteric-coated mycophenolate sodium in stable pediatric renal transplant recipients[J]. Pediatr Transplant, 2005, 9(6):780.
[8] TING L S L, PARTOVI N, LEVY R D, et al. Pharmacokinetics of mycophenolic acid and its phenolic-glucuronide and ACYl glucuronide metabolites in stable thoracic transplant recipients[J].Ther Drug Monit, 2008, 30(3):282.
[9] WEBER L T, LAMERSDORF T, SHIPKOVA M, et al. Area under the plasma concentration-time curve for total, but not for free, mycophenolic acid increases in the stable phase after renal transplantation:a longitudinal study in pediatric patients. German Study Group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients[J]. Ther Drug Monit, 1999, 21(5):498.
[10] BROOKS E, TETT S E, ISBEL N M, et al. Investigation of the association between total and free plasma and saliva mycophenolic acid concentrations following administration of enteric-coated mycophenolate sodium in adult kidney transplant recipients[J].Clin Drug Investig, 2019, 39(12):1175.
[11] FERREIRA P C L, THIESEN F V, PEREIRA A G, et al. A short overview on mycophenolic acid pharmacology and pharmacokinetics[J]. Clin Transplant, 2020, 34(8):e13997.
[12] SHAW L M, FIGURSKI M, MILONE M C, et al. Therapeutic drug monitoring of mycophenolic acid[J]. Clin J Am Soc Nephrol,2007, 2(5):1062.
[13] KLAASEN R A, BERGAN S, BREMER S, et al. Pharmacodynamic assessment of mycophenolic acid in resting and activated target cell population during the first year after renal transplantation[J].Br J Clin Pharmacol, 2020, 86(6):1100.
[14] GLANDER P, WAISER J, HAMBACH P, et al. Inosine5'-monophosphate dehydrogenase activity for the longitudinal monitoring of mycophenolic acid treatment in kidney allograft recipients[J]. Transplantation, 2021, 105(4):916.
[15] MD DOM Z I, COLLER J K, CARROLL R P, et al. Mycophenolic acid concentrations in peripheral blood mononuclear cells are associated with the incidence of rejection in renal transplant recipients[J]. Br J Clin Pharmacol, 2018, 84(10):2433.
[16] KUYPERS D R J, LE MEUR Y, CANTAROVICH M, et al.Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation[J]. Clin J Am Soc Nephrol,2010, 5(2):341.
[17] FUSS I J, KANOF M E, SMITH P D, et al. Isolation of whole mononuclear cells from peripheral blood and cord blood[J].Curr Protoc Immunol, 2009, Chapter 7:7.1.1.
[18] CHEN B, LU J Q, SHAO K, et al. Establishment of a liquid chromatography-tandem mass spectrometry method for the determination of immunosuppressant levels in the peripheral blood mononuclear cells of Chinese renal transplant recipients[J].Ther Drug Monit, 2020, 42(5):686.
[19] ZHANG D P, CHOW D S. Clinical pharmacokinetics of mycophenolic acid in hematopoietic stem cell transplantation recipients[J]. Eur J Drug Metab Pharmacokinet, 2017, 42(2):183.
[20] SALVADORI M, HOLZER H, DE MATTOS A, et al. Entericcoated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients[J].Am J Transplant, 2004, 4(2):231.
[21] FUKUDA T, GOEBEL J, TH?GERSEN H, et al. Inosine monophosphate dehydrogenase(IMPDH)activity as a pharmacodynamic biomarker of mycophenolic acid effects in pediatric kidney transplant recipients[J]. J Clin Pharmacol,2011, 51(3):309.
[22] WINNICKI W, FICHTENBAUM A, MITULOVI?G, et al. Individualization of mycophenolic acid therapy through pharmacogenetic, pharmacokinetic and pharmacodynamic testing[J]. Biomedicines, 2022, 10(11):2882.
[23] LI H, MAGER D E, SANDMAIER B M, et al. Pharmacokinetic and pharmacodynamic analysis of inosinemono phosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil[J]. Biol Blood Marrow Transplant, 2014, 20(8):1121.
基本信息:
DOI：10.19577/j.1007-4406.2025.06.001
中图分类号:R699.2
引用信息:
[1]陆韵竹,陆佳倩,邵琨,等.肾移植患者外周血单个核细胞内霉酚酸暴露量与次黄嘌呤单核苷酸脱氢酶活性的相关性研究[J].中国临床药学杂志,2025,34(06):401-407.DOI:10.19577/j.1007-4406.2025.06.001.
基金信息:
国家自然科学基金（编号81973387）
2025-06-25
2025-06-25