肾移植患者麦考酚酸的药动学和遗传多态性研究
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摘要
吗替麦考酚酯(MMF)是免疫抑制剂麦考酚酸(MPA)的吗啉乙酯前体药物，该药与钙调素抑制剂和皮质激素合用，被广泛应用防治肾脏、心脏和肝脏器官移植后的免疫排斥反应。吗替麦考酚酯口服后可迅速吸收并水解为活性代谢产物麦考酚酸。MPA是强效的、非竞争性和可逆性的次黄嘌呤核苷单磷酸脱氢酶(IMPDH)抑制剂，能够抑制鸟嘌呤核苷的从头合成途径使之不能形成DNA。T和B淋巴细胞的增殖严格依赖于嘌呤的从头合成途径，而其他的细胞可以利用补救途径，因此MPA具有抑制淋巴细胞增殖的作用。MPA随后在尿苷二磷酸葡糖醛基转移酶(UGT)的作用下，转化为麦考酚酸葡糖醛酸化物(MPAG)和酰基化麦考酚酸葡糖醛酸化物(AcMPAG)。
关于是否有必要对MPA进行治疗药物监测，目前国际上认可的结论是，由于MPA的浓度在人群中的个体差异极大，且移植病人联用大量药物，因此进行治疗药物监测，可能对改善临床治疗效果有帮助，尤其是对处于排异高风险期的病人。至于在普遍人群中开展MPA治疗药物监测的实际价值，则需要正在进行的大量国际多中心临床随机化实验加以评估。
本研究首先建立了等度洗脱、在线柱后衍生化同时测定总的MMF、MPA、MPAG和AcMPAG的高效液相色谱法。药物血浆与尿液浓度测定的预处理方法分别采用乙腈蛋白沉淀法和甲醇稀释的方法。色谱条件：Agilent ZORBAXRX-C8(250×4.6 mm，5μm)；柱温：45℃；流动相：甲醇-0.1％三氟乙酸(55-45，v／v)，流速：1.0 mL／min；柱后添加0.2 mol／L NaOH溶液，流速0.15 mL／min。MPAG采用紫外检测，检测波长为295 nm；MMF、MPA和AcMPAG采用荧光检测，荧光激发波长343 nm，发射波长425 nm。MMF、MPA、MPAG和AcMPAG的血浆浓度分别在0.04-1.00μg／mL、0.1-40.0μg／mL、10-150μg／mL和0.10-5.00μg／mL，尿液浓度分别在0.075-1.000μg／mL、0.10-10.00μg／mL、20-400μg／mL和0.25-10.00μg／mL范围内线性关系良好。本研究所建立的方法，结果准确可重现，能用于MMF及相关物质的药动学研究及常规血药浓度监测。
其次，本研究采用多中心临床实验方法，较为系统地考察了中国稳定期首次肾移植患者中MPA及其代谢物的药动学特征。对43名肾移植患者的初步研究结果表明：
该人群的MPA和MPAG的AUC_(0-12h)小于国外人群，且MMF剂量也远小于国外人群；
AcMPAG的药动学数据在国内外不同人群中都存在较大的个体差异，但尚未发现中国人群的AcMPAG体内水平显著高于其他人群；
该人群的游离MPA浓度高于国外人群数据，由于游离的MPA是体内真正发挥药理效应的组分，可能因此导致中国人群以较小的MMF服用剂量，发挥了与国外推荐剂量相当的药理效应。
此外，本研究还考察了ABCC2 G1249A、UGT1A9-118(dT)9／10、UGT287C802T、ABCC2 C-24T和SLCO183 T334G这五个位点在中国汉族肾移植患者中的频率分布，并分析了上述基因多态性对MPA及其代谢物AUC_(0-12h)的影响。本研究发现，SLCO183 T334G的分布与HapMap分布存在一定差异。通过比较不同分型的药动学数据，尽管都未达到统计学上的显著性差异，但我们发现对于UGT1A9-118(dT)9／10位点，杂合型突变(9T／10T)病人与野生型(9T／9T)病人相比，游离MPA AUC_(0-12h)约高30％；UGT287 C802T位点T／T分型病人的游离浓度比其它分型约低50％；SLCO183 T334G位点T／G分型病人AcMPAG AUC_(0-12h)分别比T／T与G／G分型病人的数据约高33％和44％。由于AUC_(0-12h)代表了药物在体内的实际暴露量，与药效存在相关性，因此提示具有上述3个基因分型的病人在临床用药时，需要严密监控临床生理指标，并根据实际情况调整用药剂量。
Mycophenolate mofetil (MMF), a morpholino ethyl ester of mycophenolic acid(MPA), in combination with calcineurin inhibitors and corticosteroids, is currentlywidely used and indicated for the prophylaxis of organ rejection in patients receivingallogeneic renal, cardiac or hepatic transplants. Mycophenolate mofetil is rapidlyabsorbed following oral administration and hydrolyzed to form MPA, which is theactive metabolite. MPA is a potent, selective, uncompetitive, and reversible inhibitorof inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the denovo pathway of guanosine nucleotide synthesis without incorporation into DNA.Because T- and B-lymphocytes are critically dependent for their proliferation on denovo synthesis of purines, whereas other cell types can utilize salvage pathways,MPA has potent cytostatic effects on lymphocytes. MPA is then metabolized to7-O-mycophenolic acid glucuronide (MPAG) and acyl glucuronide metabolite ofMPA (AcMPAG) by means of uridine diphosphate glucuronosyltransferase (UGT).
Regarding to the controversy of TDM for MPA, it was agreed that because ofinterpatient variability and the influence of concomitant immunosuppressants, TDMmight help optimize outcomes, especially in patients at higher risk of rejection. Thevalue of TDM in the general transplant population will be assessed from large,ongoing, randomized studies.
First of all, an isocratic high performance liquid chromatographic assay withonline postcolumn derivation was established for determining total concentration ofMMF, MPA, MPAG, and AcMPAG in human plasma and urine. Plasma sampleswere subjected to protein precipitation and urine samples were diluted by methanol.Agilent ZORBAX RX-C8 (250×4.6 mm, 5μm) was used as the analytical columnand maintained at 45℃. The mobile phase consisted of a mixture of methanol:0.1%trifluoroacetic acid (55:45, v/v) pumped at a flow rate of 1.0 mL/min. Regarding to thepostcolumn derivatization, another HPLC pump was added to deliver 0.2 mol/LNaOH at a flow rate of 0.15 mL/min. MPAG was determined by UV absorbance andthe detection wavelength was set at 295nm while MMF, MPA, and AcMPAG weremeasured by fluorescence detection withλex 343 nm andλem 425 nm. Thecalibration curves for each analyte were linear over the range of 0.04-1.00μg/mL,0.1-40.0μg/mL, 10-150μg/mL, and 0.10-5.00μg/mL for MMF, MPA, MPAG,and AcMPAG in human plasma. The urine calibration curves were linear over 0.075- 1.000μg/mL, 0.10-10.00μg/mL, 20-400μg/mL, and 0.25-10.00μg/mL for eachanalyte. The methods reported were found to be accurate and reproducible forquantifying the level of MMF and related compounds, and can thus be used forclinical pharmacokinetic studies and for therapeutic drug monitoring.
Secondly, the pharmacokinetic characteristics of MPA and related metabolites in43 Chinese de novo stable renal transplant recipients administrated with MMF from amulti-center clinical trial were systematically investigated. The results suggested that:
Total plasma MPA and MPAG AUC_(0-12h) in Chinese patients taking much lowerdoses of MMF were also lower than previous reports conducted in foreignpatients.
Considerable intra-and inter-patient variability in pharmacokinetic parameters ofAcMPAG have been observed in renal allograft recipients, however nosignificant higher exposure of AcMPAG was found in Chinese recipients.
The plasma concentration of free MPA, which is the pharmacologically activeform of the drug, was higher than that from foreigh population. Therefore lowerdose of MMF for Chinese population could exert equivalent effect with standarddose.
The distribution and effect of ABCC2 G1249A, UGT1A9-118(dT)9/10,UGT2B7 C802T, ABCC2 C-24T, and SLCO1B3 T334G polymorphism on thepharmacokinetics of MPA and its metabolites in Chinese renal transplant recipientswere also investigated. Results showed the distribution of SLCO1B3 T334G wasdifferent from that of HapMap Project. Although pharmacokinetic parameters did notshow statistical significance in different genotypes, it was worth noting that theAUC_(0-12h) level of free MPA was obviously higher about 30% in UGT1A9-118 (dT)9/10 9T/10T genotype carriers compared with that in 9T/9T genotype. Similarly, theAUC_(0-12h) level of free MPA was obviously lower about 50% in UGT2B7 C802T T/Tgenotype carriers compared with that in other genotypes. In addition, the AUC_(0-12h)level of AcMPAG was higher about 33% and 44% in SLCO1B3 T334G T/Ggenotype carriers compared with that in T/T and G/G genotype, respectively.AUC_(0-12h) reflects the actual drug exposure and is related to pharmacodynamics.Therefore, the patients with genotypes mentioned above, should be monitored forclinical physiological index, and the dose of MMF should be adjusted according to the actual conditions.
关于是否有必要对MPA进行治疗药物监测，目前国际上认可的结论是，由于MPA的浓度在人群中的个体差异极大，且移植病人联用大量药物，因此进行治疗药物监测，可能对改善临床治疗效果有帮助，尤其是对处于排异高风险期的病人。至于在普遍人群中开展MPA治疗药物监测的实际价值，则需要正在进行的大量国际多中心临床随机化实验加以评估。
本研究首先建立了等度洗脱、在线柱后衍生化同时测定总的MMF、MPA、MPAG和AcMPAG的高效液相色谱法。药物血浆与尿液浓度测定的预处理方法分别采用乙腈蛋白沉淀法和甲醇稀释的方法。色谱条件：Agilent ZORBAXRX-C8(250×4.6 mm，5μm)；柱温：45℃；流动相：甲醇-0.1％三氟乙酸(55-45，v／v)，流速：1.0 mL／min；柱后添加0.2 mol／L NaOH溶液，流速0.15 mL／min。MPAG采用紫外检测，检测波长为295 nm；MMF、MPA和AcMPAG采用荧光检测，荧光激发波长343 nm，发射波长425 nm。MMF、MPA、MPAG和AcMPAG的血浆浓度分别在0.04-1.00μg／mL、0.1-40.0μg／mL、10-150μg／mL和0.10-5.00μg／mL，尿液浓度分别在0.075-1.000μg／mL、0.10-10.00μg／mL、20-400μg／mL和0.25-10.00μg／mL范围内线性关系良好。本研究所建立的方法，结果准确可重现，能用于MMF及相关物质的药动学研究及常规血药浓度监测。
其次，本研究采用多中心临床实验方法，较为系统地考察了中国稳定期首次肾移植患者中MPA及其代谢物的药动学特征。对43名肾移植患者的初步研究结果表明：
该人群的MPA和MPAG的AUC_(0-12h)小于国外人群，且MMF剂量也远小于国外人群；
AcMPAG的药动学数据在国内外不同人群中都存在较大的个体差异，但尚未发现中国人群的AcMPAG体内水平显著高于其他人群；
该人群的游离MPA浓度高于国外人群数据，由于游离的MPA是体内真正发挥药理效应的组分，可能因此导致中国人群以较小的MMF服用剂量，发挥了与国外推荐剂量相当的药理效应。
此外，本研究还考察了ABCC2 G1249A、UGT1A9-118(dT)9／10、UGT287C802T、ABCC2 C-24T和SLCO183 T334G这五个位点在中国汉族肾移植患者中的频率分布，并分析了上述基因多态性对MPA及其代谢物AUC_(0-12h)的影响。本研究发现，SLCO183 T334G的分布与HapMap分布存在一定差异。通过比较不同分型的药动学数据，尽管都未达到统计学上的显著性差异，但我们发现对于UGT1A9-118(dT)9／10位点，杂合型突变(9T／10T)病人与野生型(9T／9T)病人相比，游离MPA AUC_(0-12h)约高30％；UGT287 C802T位点T／T分型病人的游离浓度比其它分型约低50％；SLCO183 T334G位点T／G分型病人AcMPAG AUC_(0-12h)分别比T／T与G／G分型病人的数据约高33％和44％。由于AUC_(0-12h)代表了药物在体内的实际暴露量，与药效存在相关性，因此提示具有上述3个基因分型的病人在临床用药时，需要严密监控临床生理指标，并根据实际情况调整用药剂量。
Mycophenolate mofetil (MMF), a morpholino ethyl ester of mycophenolic acid(MPA), in combination with calcineurin inhibitors and corticosteroids, is currentlywidely used and indicated for the prophylaxis of organ rejection in patients receivingallogeneic renal, cardiac or hepatic transplants. Mycophenolate mofetil is rapidlyabsorbed following oral administration and hydrolyzed to form MPA, which is theactive metabolite. MPA is a potent, selective, uncompetitive, and reversible inhibitorof inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the denovo pathway of guanosine nucleotide synthesis without incorporation into DNA.Because T- and B-lymphocytes are critically dependent for their proliferation on denovo synthesis of purines, whereas other cell types can utilize salvage pathways,MPA has potent cytostatic effects on lymphocytes. MPA is then metabolized to7-O-mycophenolic acid glucuronide (MPAG) and acyl glucuronide metabolite ofMPA (AcMPAG) by means of uridine diphosphate glucuronosyltransferase (UGT).
Regarding to the controversy of TDM for MPA, it was agreed that because ofinterpatient variability and the influence of concomitant immunosuppressants, TDMmight help optimize outcomes, especially in patients at higher risk of rejection. Thevalue of TDM in the general transplant population will be assessed from large,ongoing, randomized studies.
First of all, an isocratic high performance liquid chromatographic assay withonline postcolumn derivation was established for determining total concentration ofMMF, MPA, MPAG, and AcMPAG in human plasma and urine. Plasma sampleswere subjected to protein precipitation and urine samples were diluted by methanol.Agilent ZORBAX RX-C8 (250×4.6 mm, 5μm) was used as the analytical columnand maintained at 45℃. The mobile phase consisted of a mixture of methanol:0.1%trifluoroacetic acid (55:45, v/v) pumped at a flow rate of 1.0 mL/min. Regarding to thepostcolumn derivatization, another HPLC pump was added to deliver 0.2 mol/LNaOH at a flow rate of 0.15 mL/min. MPAG was determined by UV absorbance andthe detection wavelength was set at 295nm while MMF, MPA, and AcMPAG weremeasured by fluorescence detection withλex 343 nm andλem 425 nm. Thecalibration curves for each analyte were linear over the range of 0.04-1.00μg/mL,0.1-40.0μg/mL, 10-150μg/mL, and 0.10-5.00μg/mL for MMF, MPA, MPAG,and AcMPAG in human plasma. The urine calibration curves were linear over 0.075- 1.000μg/mL, 0.10-10.00μg/mL, 20-400μg/mL, and 0.25-10.00μg/mL for eachanalyte. The methods reported were found to be accurate and reproducible forquantifying the level of MMF and related compounds, and can thus be used forclinical pharmacokinetic studies and for therapeutic drug monitoring.
Secondly, the pharmacokinetic characteristics of MPA and related metabolites in43 Chinese de novo stable renal transplant recipients administrated with MMF from amulti-center clinical trial were systematically investigated. The results suggested that:
Total plasma MPA and MPAG AUC_(0-12h) in Chinese patients taking much lowerdoses of MMF were also lower than previous reports conducted in foreignpatients.
Considerable intra-and inter-patient variability in pharmacokinetic parameters ofAcMPAG have been observed in renal allograft recipients, however nosignificant higher exposure of AcMPAG was found in Chinese recipients.
The plasma concentration of free MPA, which is the pharmacologically activeform of the drug, was higher than that from foreigh population. Therefore lowerdose of MMF for Chinese population could exert equivalent effect with standarddose.
The distribution and effect of ABCC2 G1249A, UGT1A9-118(dT)9/10,UGT2B7 C802T, ABCC2 C-24T, and SLCO1B3 T334G polymorphism on thepharmacokinetics of MPA and its metabolites in Chinese renal transplant recipientswere also investigated. Results showed the distribution of SLCO1B3 T334G wasdifferent from that of HapMap Project. Although pharmacokinetic parameters did notshow statistical significance in different genotypes, it was worth noting that theAUC_(0-12h) level of free MPA was obviously higher about 30% in UGT1A9-118 (dT)9/10 9T/10T genotype carriers compared with that in 9T/9T genotype. Similarly, theAUC_(0-12h) level of free MPA was obviously lower about 50% in UGT2B7 C802T T/Tgenotype carriers compared with that in other genotypes. In addition, the AUC_(0-12h)level of AcMPAG was higher about 33% and 44% in SLCO1B3 T334G T/Ggenotype carriers compared with that in T/T and G/G genotype, respectively.AUC_(0-12h) reflects the actual drug exposure and is related to pharmacodynamics.Therefore, the patients with genotypes mentioned above, should be monitored forclinical physiological index, and the dose of MMF should be adjusted according to the actual conditions.
引文
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[36] Jain A, Venkataramanan R, Kwong T, et al. Pharmacokinetics of mycophenolic acid in liver transplant patients after intravenous and oral administration of mycophenolate mofetil[J].Liver Transpl,2007,13(6):791-796.
[37] in http://www.fda.gov/cder/guidance/index.htm, FDA Home page. Guidance for Industry: Bioanalytical Method Validation, 2001.
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[39] Z.Jiao, Y. Zhong, J. Shen, Y.Q. Yu. Simple high-performance liquid chromatographic assay, with post-column derivatization, for simultaneous determination of mycophenolic acid and its glucuronide metabolite in human plasma and urine[J].Chromatographia,2005, 62(7/8):363-371.
[40] Shen J, Jiao Z, Yu YQ, Zhang M, Zhong MK. Quantification of total and free mycophenolic acid in human plasma by liquid chromatography with fluorescence detection[J].J Chromatogr B Analyt Technol Biomed Life Sci,2005,817(2):207-213.
[41] Zhong Y, Jiao Z, Yu Y. Simultaneous determination of mycophenolic acid and valproic acid based on derivatization by high-performance liquid chromatography with fluorescence detection[J].Biomed Chromatogr,2006,20(4):319-326.
[42] Cussonneau X, Bolon-Larger M, Boulieu R. Adsorption of mycophenolic acid and its phenolic glucuronide to glass, polystyrene, and polypropylene containers[J].Clin Chem,2006, 52(5):904-906.
[43] Gandhi MK, Khanna R. Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments[J].Lancet Infect Dis,2004,4(12):725-738.
[44] Biron KK. Antiviral drugs for cytomegalovirus diseases[J] .Antiviral Res,2006,71(2-3):154-163.
[45] Schacker T, Hu HL, Koelle DM, et al. Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons. A double-blind, placebo-controlled trial[J].Ann Intern Med,1998,128(1):21-28.
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[54] Basu NK, Kole L, Kubota S, Owens IS. Human UDP-glucuronosyltransferases show atypical metabolism of mycophenolic acid and inhibition by curcumin[J].Drug Metab Dispos,2004,32(7):768-773.
[55] Bernard O, Guillemette C. The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants[J].Drug Metab Dispos,2004,32(8):775-778.
[56] Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P. Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism[J].Drug Metab Dispos,2005,33(1):139-146.
[57] Miura M, Satoh S, Inoue K, et al. Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients[J].Eur J Clin Pharmacol , 2007, 63(12):1161-1169.
[58] Miura M, Kagaya H, Satoh S, et al. Influence of Drug Transporters and UGT Polymorphisms on Pharmacokinetics of Phenolic glucuronide Metabolite of Mycophenolic Acid in Japanese Renal Transplant Recipients[J].Ther Drug Monit,2008[Epub ahead of print].
[59] Betonico GN, Abbud-Filho M, Goloni-Bertollo EM, et al. Influence of UDP-Glucuronosyltransferase Polymorphisms on Mycophenolate Mofetil-Induced Side Effects in Kidney Transplant Patients[J].Transplant Proc,2008,40(3):708-710.
[60] Kagaya H, Inoue K, Miura M, et al. Influence of UGT1A8 and UGT2B7 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients[J].Eur J Clin Pharmacol,2007,63(3):279-288.
[61] Zhang WX, Chen B, Jin Z, et al. Influence of uridine diphosphate (UDP)-glucuronosyltransferases and ABCC2 genetic polymorphisms on the pharmacokinetics of mycophenolic acid and its metabolites in Chinese renal transplant recipients[J].Xenobiotica,2008,38(11):1422-1436.
[62] Ramirez J, Liu W, Mirkov S, et al. Lack of association between common polymorphisms in UGT1A9 and gene expression and activity[J].Drug Metab Dispos,2007,35(12):2149-2153.
[63] Kuypers DR, de Jonge H, Naesens M, et al. Current target ranges of mycophenolic acid exposure and drug-related adverse events: a 5-year,open-label, prospective, clinical follow-up study in renal allograft recipients[J].Clin Ther,2008,30(4):673-683.
[64] Kuypers DR, Naesens M, Vermeire S, Vanrenterghem Y. The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients[J].Clin Pharmacol Ther,2005,78(4):351-361.
[65] van Agteren M, Armstrong VW, van Schaik RH, et al. AcylMPAG plasma concentrations and mycophenolic acid-related side effects in patients undergoing renal transplantation are not related to the UGT2B7-840G>A gene polymorphism[J]. Ther Drug Monit,2008,30(4):439-444.
[66] Djebli N, Picard N, Rerolle JP, Le Meur Y, Marquet P. Influence of the UGT2B7 promoter region and exon 2 polymorphisms and comedications on Acyl-MPAG production in vitro and in adult renal transplant patients[J].PharmacogenetGenomics,2007,17(5):321-330.
[67] Naesens M, Kuypers DR, Verbeke K, Vanrenterghem Y. Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients[J].Transplantation,2006,82(8):1074-1084.
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[41] Zhong Y, Jiao Z, Yu Y. Simultaneous determination of mycophenolic acid and valproic acid based on derivatization by high-performance liquid chromatography with fluorescence detection[J].Biomed Chromatogr,2006,20(4):319-326.
[42] Cussonneau X, Bolon-Larger M, Boulieu R. Adsorption of mycophenolic acid and its phenolic glucuronide to glass, polystyrene, and polypropylene containers[J].Clin Chem,2006, 52(5):904-906.
[43] Gandhi MK, Khanna R. Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments[J].Lancet Infect Dis,2004,4(12):725-738.
[44] Biron KK. Antiviral drugs for cytomegalovirus diseases[J] .Antiviral Res,2006,71(2-3):154-163.
[45] Schacker T, Hu HL, Koelle DM, et al. Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons. A double-blind, placebo-controlled trial[J].Ann Intern Med,1998,128(1):21-28.
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[47] CellCept? [product information][R]. Nutley, NJ: Roche Laboratories Inc,December 2008:
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[49] Naesens M, Kuypers DR, Streit F, et al. Rifampin induces alterations in mycophenolic acid glucuronidation and elimination: implications for drug exposure in renal allograft recipients[J].Clin Pharmacol Ther,2006, 80 (5): 509 -521.
[50] Akhlaghi F, Patel CG, Zuniga XP, Halilovic J, Preis IS, Gohh RY.Pharmacokinetics of mycophenolic acid and metabolites in diabetic kidney transplant recipients[J].Ther Drug Monit,2006,28(1):95-101.
[51] Kuypers DR, Vanrenterghem Y, Squifflet JP, et al. Twelve-month evaluation of the clinical pharmacokinetics of total and free mycophenolic acid and its glucuronide metabolites in renal allograft recipients on low dose tacrolimus in combination with mycophenolate mofetil[J].Ther Drug Monit, 2003, 25(5):609-622.
[52] Patel CG, Harmon M, Gohh RY, Akhlaghi F. Concentrations of mycophenolic acid and glucuronide metabolites under concomitant therapy with cyclosporine or tacrolimus[J].Ther Drug Monit,2007,29(1):87-95.
[53] Gonzalez-Roncero FM, Govantes MA, Chaves VC, Palomo PP, Serra MB.Influence of renal insufficiency on pharmacokinetics of ACYL-glucuronide metabolite of mycophenolic acid in renal transplant patients[J] .Transplant Proc,2007,39(7):2176-2178.
[54] Basu NK, Kole L, Kubota S, Owens IS. Human UDP-glucuronosyltransferases show atypical metabolism of mycophenolic acid and inhibition by curcumin[J].Drug Metab Dispos,2004,32(7):768-773.
[55] Bernard O, Guillemette C. The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants[J].Drug Metab Dispos,2004,32(8):775-778.
[56] Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P. Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism[J].Drug Metab Dispos,2005,33(1):139-146.
[57] Miura M, Satoh S, Inoue K, et al. Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients[J].Eur J Clin Pharmacol , 2007, 63(12):1161-1169.
[58] Miura M, Kagaya H, Satoh S, et al. Influence of Drug Transporters and UGT Polymorphisms on Pharmacokinetics of Phenolic glucuronide Metabolite of Mycophenolic Acid in Japanese Renal Transplant Recipients[J].Ther Drug Monit,2008[Epub ahead of print].
[59] Betonico GN, Abbud-Filho M, Goloni-Bertollo EM, et al. Influence of UDP-Glucuronosyltransferase Polymorphisms on Mycophenolate Mofetil-Induced Side Effects in Kidney Transplant Patients[J].Transplant Proc,2008,40(3):708-710.
[60] Kagaya H, Inoue K, Miura M, et al. Influence of UGT1A8 and UGT2B7 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients[J].Eur J Clin Pharmacol,2007,63(3):279-288.
[61] Zhang WX, Chen B, Jin Z, et al. Influence of uridine diphosphate (UDP)-glucuronosyltransferases and ABCC2 genetic polymorphisms on the pharmacokinetics of mycophenolic acid and its metabolites in Chinese renal transplant recipients[J].Xenobiotica,2008,38(11):1422-1436.
[62] Ramirez J, Liu W, Mirkov S, et al. Lack of association between common polymorphisms in UGT1A9 and gene expression and activity[J].Drug Metab Dispos,2007,35(12):2149-2153.
[63] Kuypers DR, de Jonge H, Naesens M, et al. Current target ranges of mycophenolic acid exposure and drug-related adverse events: a 5-year,open-label, prospective, clinical follow-up study in renal allograft recipients[J].Clin Ther,2008,30(4):673-683.
[64] Kuypers DR, Naesens M, Vermeire S, Vanrenterghem Y. The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients[J].Clin Pharmacol Ther,2005,78(4):351-361.
[65] van Agteren M, Armstrong VW, van Schaik RH, et al. AcylMPAG plasma concentrations and mycophenolic acid-related side effects in patients undergoing renal transplantation are not related to the UGT2B7-840G>A gene polymorphism[J]. Ther Drug Monit,2008,30(4):439-444.
[66] Djebli N, Picard N, Rerolle JP, Le Meur Y, Marquet P. Influence of the UGT2B7 promoter region and exon 2 polymorphisms and comedications on Acyl-MPAG production in vitro and in adult renal transplant patients[J].PharmacogenetGenomics,2007,17(5):321-330.
[67] Naesens M, Kuypers DR, Verbeke K, Vanrenterghem Y. Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients[J].Transplantation,2006,82(8):1074-1084.
[68] http://www.hapmap.org.