吗替麦考酚酯分散片在早期肾移植患者中的药动学研究

Pharmacokinetics Study of Mycophenolate Mofetil Dispersible Tablets in Early Renal Transplant Patients

目的建立测定人血浆中霉酚酸(MPA)的超高效液相色谱(UPLC)方法,研究多次口服吗替麦考酚酯(MMF)分散片在早期肾移植患者中的药动学,为该药的临床合理应用提供依据。方法 15例肾移植受者口服MMF分散片,750 mg·次^(-1),q12 h,连续服用6 d后,第7天分别于服药前及服药后0.5、1、1.5、2、3、4、6、8、10、12 h采集静脉血样2 mL,采用UPLC-UV分析方法测定MPA血浆浓度。计算主要的药动学参数。结果测定方法线性范围为0.1~40μg·mL^(-1),定量下限为0.10μg·mL^(-1),术后第7天MMF分散片的主要药动学参数AUC_(0-12 h)为(24.63±9.51)μg·h·mL^(-1),ρ_(max)为(6.51±3.27)μg·mL^(-1),t_(max)为(1.83±1.30)h,ρ_0为(1.26±0.99)μg·mL^(-1),CL为(34.66±12.45)L·h^(-1)。大部分病人在给药后4~12 h血浆MPA浓度出现第2个小峰。结论本测定方法简单、快速,适用于测定人血浆中MPA的浓度。MMF分散片在早期肾移植患者体内的药动学参数个体间变异较大,常规剂量的MMF分散片在早期肾移植患者中暴露量普遍较低,建议结合MPA-AUC_(0-12 h)值调整给药剂量。

OBJECTIVE To develop an UPLC method for the determination of mycophenolic acid （MPA） for studying the phar- macokinetics of myeophenolate mofetil（MMF） dispersible tablets after multiple oral doses in early kidney transplant recipients for the rational use in the clinical practice. METHODS A total of 15 Chinese postoperative renal transplant recipients were given a multiple- dose of MMF （750 mg, q12 h） for 6 d. Their blood specimens （2 mL） were collected at 0 and 0. 5, 1, 1.5, 2, 3,4, 6, 8, 10, 12 h after drug oral administration on day 7. The concentrations of MPA in plasma were determined using UPLC-UV. The main pharmaco- kinetic parameters were assessed. RESULTS Determination of MPA had good linearity in the concentration range of 0. 1 - 40 μg·mL^-1, lower limit of quantization was 0. 10μg·mL^-1. The main pharmacokinetic parameters on day 7 of MMF dispersible tablets were as follows ： AUC0-12 h was （24. 63 ＋ 9. 51 ）μg·h·mL^-1 , ρmax was （ 6. 51 ± 3.27 ） μg·mL^-1, tmax was （ 1.83±1.30） h, P0 was （1.26±0.99）μg·mL^-1,CL was （34.66 ±12.45） L·h^-1. Most of the patients revealed a second small peak in the 4-12 h. CONCLUSION This established method is simple, rapid and suitable for determination of MPA in human plasma. Interindividual variability in AUC0-12 h, ρmax and Po values was considerable in the early renal transplant patients. The MPA exposures under the fixed dose of MMF are low. It is necessary to monitor the MPA-AUC0-12 h to guide the adjustment of drug dosage.