吗替麦考酚酯胶囊和麦考酚钠肠溶片在早期肾移植患者中的药动学

目的：探讨肾移植术后早期患者口服吗替麦考酚酯胶囊（MMF）和麦考酚钠肠溶片（EC-MPS）的药动学特点，为临床合理用药提供依据。方法：选取26例肾移植患者，按随机数字表法分为MMF组（n=13）和EC-MPS组（n=13），两组患者分别于术后第1天给予MMF（750 mg q12 h）或EC-MPS（720 mg q12 h）、他克莫司、甲泼尼龙预防排斥反应。于术后第7天的早上服药前及服药后0.5，1，1.5，2，3，4，6，8，10，12 h采集静脉血样3 mL，采用UPLC-UV分析方法测定霉酚酸（MPA）血浆浓度。以 DAS 2.0药动学软件进行药动学分析，所有与剂量相关的两组药动学参数分别进行了剂量校正（C_max/D，C₀/D，AUC_{0-12 h}/D及AUMC_{0-12 h}/D）。用SPSS 17.0软件进行统计学分析。结果：术后第7天MMF和EC-MPS的主要药动学参数t_max分别为（1.54±0.9）h和（2.19±1.56）h（P> 0.05）；C_max/D分别为（5.12±2.83）mg·L^-1·g^-1和（9.51±7.38）mg·L^-1·g^-1（P> 0.05）；AUC_{0-12 h}/D分别为（19.13±7.78）mg·h·L^-1·g^-1和（25.96±11.78）mg·h·L^-1·g^-1（P> 0.05）。两组患者的药-时曲线个体间差异均较大，大部分患者观察到有双峰现象，极个别患者观察到有多峰。MMF组和EC-MPS组患者的MPA-AUC_{0-12 h}低暴露组比例分别为84.6%和46.15%，目标暴露组比例分别为15.4%和46.15%，仅有1例EC-MPS组患者为高暴露组。结论：MMF和EC-MPS在早期肾移植患者体内的药动学个体差异较大，需要常规监测MPA-AUC_{0-12 h}，同时可结合C₀作为参考，以指导临床调整用药剂量。MMF和EC-MPS常规剂量下的MPA-AUC_{0-12 h}在早期肾移植患者中偏低，建议增加给药剂量。

Pharmacokinetics of mycophenolate mofetil and enteric-coated mycophenolate sodium in patients after early renal transplantation

OBJECTIVE To investigate the pharmacokinetics of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) in early renal transplantation patients,provide references for the rational use of drugs in the clinical practice.METHODS Twenty six renal transplantation patients were selected and divided into MMF group (n=13) or EC-MPS group (n=13) according to the random digital table method.The patients respectively received MMF (750 mg q12h) or EC-MPS (720 mg q12h),tacrolimus and methylprednisolone to prevent rejection.The blood samples were collected at pre-dose,0.5,1,1.5,2,3,4,6,8,10,12 h after oral medication in the morning of postoperative day 7.UPLC-UV method was employed to determine the plasma concentration of MPA.Pharmacokinetic parameters of MPA were calculated by software DAS 2.0,dose calibration was performed in two groups with dose dependent pharmacokinetic parameters(C_max/D,C₀/D,AUC_{0-12 h}/D and AUMC_{0-12 h}/D).Statistical analysis was performed with SPSS 17.0 software.RESULTS On postoperative day 7,the main pharmacokinetic parameters of MMF and EC-MPS were as follows:t_max, (1.54±0.9) h and (2.19±1.56) h (P>0.05); C_max/D,(5.12±2.83) mg·L^-1·g^-1and (9.51±7.38) mg·L^-1·g^-1 (P>0.05); AUC_{0-12 h}/D,(19.13±7.78) mg·h·L^-1·g^-1 and (25.96±11.78) mg·h·L^-1·g^-1 (P> 0.05).Significant difference was observed in concentration-time curves of MPA of individuals between the two groups.Two peaks on concentration-time curve of the drug were observed in most patients,some patients even showed multiple peaks of MPA.MPA-AUC_{0-12 h} low exposures were 84.6% and 46.15% for MMF and EC-MPS,target exposures were 15.4% and 46.15%,respectively.Only 1 patient in group EC-MPS showed high exposure.CONCLUSION Individual difference has been observed for pharmacokinetics between MMF and EC-MPS in early renal transplantation patients.It is necessary to monitor the MPA-AUC_{0-12 h} and combine with C₀ during medication to guide drug dose adjustment.The drug dose should be increased because the MPA exposures at conventional doses of MMF and EC-MPS are low in early renal transplantation patients.