The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGTIA9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients
The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGTIA9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients
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DOI：
10.1016/j.clpt.2005.06.007
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发表时间：
2005-10-01
影响因子：
6.7
通讯作者：
Vanrenterghem, Y
中科院分区：
文献类型：
--
作者：
Kuypers, DRJ;Naesens, M;Vanrenterghem, Y
背景：麦考酚酸是一种用于肾移植的有效免疫抑制药物，它广泛地被几种尿苷二磷酸-葡萄糖醛酸基转移酶(UGT)作用于葡萄糖醛酸，生成无活性的7-O-葡萄糖醛酸苷，并在较小程度上转化为具有药理活性的酰基葡萄糖醛酸苷。使用人肝微粒体的实验表明，UGT1A9启动子区域的T-275A和C-2152T单核苷酸多态(SNPs)与UGT1A9在肝脏中的高表达和体外对MPA的葡萄糖醛酸化活性增加相关。对95例肾移植受者进行了UGT1A9基因启动子区T-275A和C-2152T单核苷酸多态及UGT1A9*3编码区突变频率较低的研究。评估这些UGT1A9单核苷酸多态对早期临床药代动力学的影响。仅在每天服用2g霉酚酸酯的患者中，携带T-275A和/或C-2152T多态(或两者都携带)的患者与未携带T-275A或C-2152T多态(0-12小时的浓度-时间曲线下面积，31.7+/-17.6 mg中心点h/L对63.6+/-30.9 mg中心点h/L[P=0.009]；服药前血浆浓度谷值，1.23+/-1.25 mg/L对2.84+/-1.64 mg/L[P=0.04])相比，暴露于甲氧西林的水平较低。当两个或两个UGT1A9启动子区SNP同时存在时，6-12小时的部分MPAAUC(6-12)和0-12小时的部分MAPAAUC(6-12)与剂量间隔AUC的比率降低(AUC(6-12)，6.2+/-5.4 mg中心点h/L vs 21.5+/-14.9 mg中心点h/L[P=0.002]；结论：UGT1A9基因启动子T-275A和C-2152TSNPs与每日服用2g霉酚酸酯的肾移植患者的甲孕酮暴露显著减少有关，这种影响的部分原因是阻断了甲孕酮的肝-肠循环。
Background: Mycophenolic acid (MPA), an effective immunosuppressive drug used in renal transplantation, is extensively glucuronidated by several uridine diphosphate-glucuronosyltransferases (UGTs) into an inactive 7-O-glucuronide and, to a lesser extent, into a pharmacologically active acyl-glucuronide. Experiments using human liver microsomes have shown that T-275A and C-2152T single-nucleotide polymorphisms (SNPs) of the UGT1A9 promoter region are associated with higher hepatic expression of UGT1A9 and increased in vitro glucuronidation activity for MPA.Methods. The distribution of UGT1A9 promoter region T-275A and C-2152T SNPs and the less frequent UGT1A9*3 coding region mutation, which results in decreased in vitro activity, was determined in 95 de novo renal recipients. The impact of these UGT1A9 SNPs on early clinical MPA pharmacokinetics was evaluated.Results. Only in patients taking 2 g mycophenolate mofetil daily was a decreased MPA exposure observed in those who carried either the T-275A or the C-2152Tpolymorphism (or both) compared with those who did not (area under concentration-time curve [AUC] from 0 to 12 hours, 31.7 +/- 17.6 mg center dot h/L versus 63.6 +/- 30.9 mg center dot h/L [P =.009]; predose trough plasma concentration, 1.23 +/- 1.25 mg/L versus 2.84 +/- 1.64 mg/L [P =.04]). The partial MPA AUC from 6 to 12 hours (AUC(6-12))-an estimate of MPA enterohepatic recirculation-and the ratio between partial MPA AUC(6-12) and dose-interval AUC from 0 to 12 hours decreased when either or both UGT1A9 promoter region SNPs were present (AUC(6-12), 6.2 +/- 5.4 mg center dot h/L versus 21.5 +/- 14.9 mg center dot h/L [P =.002]; ratio, 18.4% +/- 7.8% versus 31.7% +/- 8.8% [P =.002]).Conclusion: The T-275A and C-2152TSNPs of the UGT1A9gene promoter are associated with significantly lower MPA exposure in renal recipients treated with 2 g mycophenolate mofetil daily, and part of this effect is caused by interruption of enterohepatic recirculation of MPA.