Influence of UGT1A7 and UGT1A9 intronic 1399 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients
Influence of UGT1A7 and UGT1A9 intronic 1399 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients
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DOI：
10.1097/ftd.0b013e3180686146
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发表时间：
2007-06-01
影响因子：
2.5
通讯作者：
Suzuki, Toshio
中科院分区：
文献类型：
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作者：
Inoue, Kazuyuki;Miura, Masatomo;Suzuki, Toshio
UGT1A7和UGT1A9是参与麦考酚酸葡萄糖醛酸化反应的尿苷二磷酸-葡萄糖醛酸基转移酶亚型。本研究的目的是阐明日本成人肾移植受者UGT1A7和UGT1A9内含子1399基因的甲孕酮药代动力学。80例受试者在指定时间(上午9：00和晚上9：00)每隔12小时重复给予霉酚酸酯和他克莫司联合免疫抑制治疗。肾移植后第28天，用高效液相色谱法测定血浆甲孕酮浓度。所有患者均为UGT1A9 98TT/-275TT/-2152CC和UGT1A10 177GG/605CC。UGT1A7*1/*1、*1/*2、*1/*3、*2/*3、*2/*3和*3/*3分别为35例(43.8%)、5例(6.2%)、28例(35.0%)、8例(10.0%)和4例(5.0%)，UGTIA9 I399C/C、C/T和T/T分别为12例(15.0%)、33例(41.2%)、80例日本受者中35例(43.8%)。UGT1A7和UGTIA9内含子1399基因型组之间的甲孕酮药代动力学差异无统计学意义。UGT1A7*1/*1、*1/*2、*1/*3、*2/*3和*3/*3组0-12小时血药浓度-时间曲线下的平均剂量调整面积分别为95、98、99、88和86 ng/m L/mg(P=0.9475)。UGTIA91399C/C、C/T和T/T的甲孕酮平均剂量调整后AUC值(0.6937~12)分别为87、99和95 ng·h/mL/mg(P=0.05)。剂量调整后，UGTIA91399C/C、C/T和T/T的Mpa谷值分别为5.4、5.5和4.7 ng/m L/mg(P=0.5845)。虽然已知UGT1A7*3和UGTIA9 I399C/C在体外研究中具有低活性的变体，但它们在体内并没有降低MPA葡萄糖醛酸化活性。UGT1A7和UGTIA9 1399基因多态并不影响甲孕酮药代动力学的个体间差异。
UGT1A7 and UGT1A9 are uridine diphosphate-glucuronosyltransferase isoforms involved in the glucuronidation of mycophenolic acid (MPA). The aim of this study was to elucidate MPA pharmacokinetics in UGT1A7 and UGT1A9 intronic 1399 genotypes in Japanese adult renal transplant recipients. Eighty recipients were given repeated doses of combination immunosuppressive therapy consisting of mycophenolate mofetil and tacrolimus every 12 hours at a designated time (9:00 Am and 9:00 Pm). On day 28 after renal transplantation, plasma MPA concentrations were measured by high-performance liquid chromatography. All patients had UGT1A9 98TT/-275TT/-2152CC and UGT1A10 177GG/605CC genotypes. The UGT1A7*1/*1, *1/*2, *1/*3, *2/*3, and *3/*3 genotypes were detected in 35 (43.8%), five (6.2%), 28 (35.0%), eight (10.0%), and four (5.0%) patients, respectively, and the UGTIA9 I399C/C, C/T, and T/T genotypes were detected in 12 (15.0%), 33 (41.2%), and 35 (43.8%) patients of the 80 Japanese recipients. There were no significant differences in MPA pharmacokinetics among UGT1A7 or UGTIA9 intronic 1399 genotype groups. The mean dose-adjusted area under the plasma concentration-time curve from zero to 12 hours (AUC(0-12)) of MPA in UGT1A7*1/*1, *1/*2, *1/*3, *2/*3, and *3/*3 were 95, 98, 99, 88, and 86 ng(.)h/mL/mg, respectively (P = 0.9475). The mean dose-adjusted AUC(0-12) of MPA in UGTIA9 1399C/C, C/T, and T/T were 87, 99, and 95 ng(.)h/mL/mg, respectively (P = 0.6937). The dose-adjusted trough levels of MPA in UGTIA9 1399C/C, C/T, and T/T were 5.4, 5.5, and 4.7 ng/mL/mg (P = 0.5845). Although UGT1A7*3 and UGTIA9 I399C/C are known to have low-activity variants when studied in vitro, they do not have reduced in vivo MPA glucuronidation activity. UGT1A7 and UGTIA9 1399 polymorphisms do not contribute to interindividual differences in MPA pharmacokinetics.