Kagaya H, Miura M, Satoh S, Inoue K, Saito M, Inoue T, Habuchi T, Suzuki T
Department of Pharmacy, Akita University Hospital, Akita, Japan.
J Clin Pharm Ther. 2008 Apr;33(2):193-201. doi: 10.1111/j.1365-2710.2008.00906.x.
The aim of this study was to investigate drug interactions between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF) and tacrolimus, as well as the impact of CYP3A5 and UGT2B7 genetic polymorphisms on these drug interactions in 71 Japanese renal transplant recipients.
Recipients received combination immunosuppressive therapy consisting of tacrolimus and MMF. On day 28 after transplantation, the concentrations of MPA and tacrolimus were measured by high-performance liquid chromatography and microparticle enzyme immunoassay respectively.
Acute rejection was over twice more common in recipients with a total area under the observed plasma concentration-time curve (AUC(0-12)) of MPA <70 microg x h/mL than in those with higher values AUC(0-12) values (17% vs. 7%). Using this cut-off AUC value, sensitivity was 70.6% and specificity 55.6% for acute rejection (AR). There was no change in AUC(0-12), maximum plasma concentration, trough plasma concentration, or oral clearance of tacrolimus with variation in dosage or AUC of MPA. There were also no significant differences in the MPA pharmacokinetic parameters among three tacrolimus C(0) groups: 5 < or = C(0) < 10, 10 < or = C(0) < 15 and 15 < or =C(0) < 20 ng/mL. Furthermore, there were no significant differences in MPA pharmacokinetic parameters between the UGT2B7*1/*1 and 1/2 genotype groups having the CYP3A51 allele or the CYP3A53/*3 genotype.
Therapeutic dosages of MMF, do not significantly influence tacrolimus pharmacokinetics, and vice versa. Consequently, MPA and tacrolimus can be safely combined; however, it is necessary to monitor the plasma concentrations of each immunosuppressive agent to minimize acute rejection.
本研究旨在调查霉酚酸（MPA）（霉酚酸酯（MMF）的活性代谢产物）与他克莫司之间的药物相互作用，以及CYP3A5和UGT2B7基因多态性对71例日本肾移植受者中这些药物相互作用的影响。
受者接受由他克莫司和MMF组成的联合免疫抑制治疗。移植后第28天，分别通过高效液相色谱法和微粒体酶免疫测定法测量MPA和他克莫司的浓度。
MPA的观察血浆浓度-时间曲线下总面积（AUC(0-12)）<70μg·h/mL的受者急性排斥反应的发生率是AUC(0-12)值较高者的两倍多（17%对7%）。使用该临界AUC值，急性排斥反应（AR）的敏感性为70.6%，特异性为55.6%。随着MPA剂量或AUC的变化，他克莫司的AUC(0-12)、最大血浆浓度、谷血浆浓度或口服清除率没有变化。在三个他克莫司C(0)组（5≤C(0)<10、10≤C(0)<15和15≤C(0)<20 ng/mL）中，MPA的药代动力学参数也没有显著差异。此外，具有CYP3A51等位基因的UGT2B71/1和1/2基因型组或CYP3A53/*3基因型组之间的MPA药代动力学参数也没有显著差异。
MMF的治疗剂量不会显著影响他克莫司的药代动力学，反之亦然。因此，MPA和他克莫司可以安全联合使用；然而，有必要监测每种免疫抑制剂的血浆浓度，以尽量减少急性排斥反应。
