Ensom Mary H H, Partovi Nilufar, Decarie Diane, Dumont Randall J, Fradet Guy, Levy Robert D
Faculty of Pharmaceutical Sciences, Department of Pharmacy 0B7, The University of British Columbia, Children's & Women's Health Center of British Columbia, 4480 Oak Street, Vancouver, BC, Canada, V6H 3V4.
Ther Drug Monit. 2002 Apr;24(2):310-4. doi: 10.1097/00007691-200204000-00013.
Mycophenolate mofetil (MMF) use is increasing in solid organ transplantation. Mycophenolic acid (MPA), the active metabolite of MMF, is highly protein bound and only free MPA is pharmacologically active. The average MPA free fraction in healthy adult individuals, stable renal transplant recipients, and heart transplant recipients is approximately 2 to 3%. However, no data are currently available on MPA protein binding in stable lung transplant recipients and little is known regarding MPA's pharmacokinetic characteristics after lung transplantation. The purpose of this study was to characterize the pharmacokinetic profile and protein binding of MPA in this patient population. Seven patients were entered into the study. On administration of a steady-state morning MMF dose, blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 8, 9, 10, and 12 hours post-dose. Total MPA concentrations were measured by a validated HPLC method with UV detection and followed by ultrafiltration of pooled samples for free MPA concentrations. Area under the curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), trough concentration (Cmin), free fraction (f), and free MPA AUC were calculated by traditional pharmacokinetic methods. Patient characteristics included; 3 males and 4 females, an average of 4.4 years post-lung transplant (range, 0.3-11.5 yr), mean (+/- SD) age of 50 +/- 10 years and weight 69 +/- 20 kg. Mean albumin concentration was 37 +/- 3 g/L and serum creatinine was 142 +/- 49 micromol/L. All patients were on cyclosporine and prednisone. MMF dosage ranged from 1 to 3 g daily (35.5 +/- 14.1 mg/kg/d; range, 15.2-60.0 mg/kg/d). Mean (+/- SD) AUC was 45.78 +/- 18.35 microg.h/mL (range, 16.56-74.22 microg.h/mL), Cmax was 17.37 +/- 7.69 microg/mL (range, 4.92-26.63 microg/mL), Tmax was 1.2 +/- 0.4 hours (range, 1.0-2.0 h), Cmin was 3.12 +/- 1.41 microg/mL (range, 1.47-4.82 microg/mL), f was 2.90 +/- 0.56% (range, 2.00-3.40%), and free MPA AUC was 1.29 +/- 0.50 microg.h/mL (range, 0.54-1.88 microg.h/mL). This is the first study to determine these pharmacokinetic characteristics of MPA in the lung transplant population. Further studies should focus on identification of MMF dosing strategies that optimize immunosuppressive efficacy and minimize toxicity in lung allograft recipients.
霉酚酸酯（MMF）在实体器官移植中的应用日益增加。霉酚酸（MPA）是MMF的活性代谢产物，与蛋白质高度结合，只有游离MPA具有药理活性。健康成年个体、稳定的肾移植受者和心脏移植受者中MPA的平均游离分数约为2%至3%。然而，目前尚无关于稳定的肺移植受者中MPA蛋白结合的数据，且对于肺移植后MPA的药代动力学特征知之甚少。本研究的目的是描述该患者群体中MPA的药代动力学特征和蛋白结合情况。七名患者进入该研究。在给予稳态早晨MMF剂量后，于给药后0、1、2、3、4、5、6、8、9、10和12小时采集血样。通过经过验证的带有紫外检测的高效液相色谱法测量总MPA浓度，随后对混合样本进行超滤以测定游离MPA浓度。通过传统药代动力学方法计算曲线下面积（AUC）、峰值浓度（Cmax）、达峰时间（Tmax）、谷浓度（Cmin）、游离分数（f）和游离MPA AUC。患者特征包括：3名男性和4名女性，肺移植后平均4.4年（范围为0.3 - 11.5年），平均（±标准差）年龄为50 ± 10岁，体重69 ± 20 kg。平均白蛋白浓度为37 ± 3 g/L，血清肌酐为142 ± 49 μmol/L。所有患者均接受环孢素和泼尼松治疗。MMF剂量范围为每日1至3 g（35.5 ± 14.1 mg/kg/d；范围为15.2 - 60.0 mg/kg/d）。平均（±标准差）AUC为45.78 ± 18.35 μg·h/mL（范围为16.56 - 74.22 μg·h/mL），Cmax为17.37 ± 7.69 μg/mL（范围为4.92 - 26.63 μg/mL），Tmax为1.2 ± 0.4小时（范围为1.0 - 2.0小时），Cmin为3.12 ± 1.41 μg/mL（范围为1.47 - 4.82 μg/mL），f为2.90 ± 0.56%（范围为2.00 - 3.40%），游离MPA AUC为1.29 ± 0.50 μg·h/mL（范围为0.54 - 1.88 μg·h/mL）。这是第一项确定肺移植群体中MPA这些药代动力学特征的研究。进一步的研究应侧重于确定优化肺移植受者免疫抑制疗效并将毒性降至最低的MMF给药策略。
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