Inoue Kazuyuki, Miura Masatomo, Satoh Shigeru, Kagaya Hideaki, Saito Mitsuru, Habuchi Tomonori, Suzuki Toshio
Department of Pharmacy, Akita University Hospital, Akita, Japan.
Ther Drug Monit. 2007 Jun;29(3):299-304. doi: 10.1097/FTD.0b013e3180686146.
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 I399 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 UGT1A9 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 UGT1A9 intronic I399 genotype groups. The mean dose-adjusted area under the plasma concentration-time curve from zero to 12 hours (AUC0-12) of MPA in UGT1A71/*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 AUC0-12 of MPA in UGT1A9 I399C/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 UGT1A9 I399C/C, C/T, and T/T were 5.4, 5.5, and 4.7 ng/mL/mg (P = 0.5845). Although UGT1A73 and UGT1A9 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 UGT1A9 I399 polymorphisms do not contribute to interindividual differences in MPA pharmacokinetics.
UGT1A7和UGT1A9是参与霉酚酸（MPA）葡萄糖醛酸化作用的尿苷二磷酸葡萄糖醛酸基转移酶同工型。本研究的目的是阐明日本成年肾移植受者中UGT1A7和UGT1A9内含子I399基因型的MPA药代动力学。80名受者在指定时间（上午9:00和晚上9:00）每12小时重复给予由霉酚酸酯和他克莫司组成的联合免疫抑制治疗。肾移植后第28天，通过高效液相色谱法测定血浆MPA浓度。所有患者均具有UGT1A9 98TT/-275TT/-2152CC和UGT1A10 177GG/605CC基因型。分别在35名（43.8%）、5名（6.2%）、28名（35.0%）、8名（10.0%）和4名（5.0%）患者中检测到UGT1A7*1/*1、*1/*2、*1/*3、*2/3和3/3基因型，在80名日本受者中，分别有12名（15.0%）、33名（41.2%）和35名（43.8%）患者检测到UGT1A9 I399C/C、C/T和T/T基因型。UGT1A7或UGT1A9内含子I399基因型组之间的MPA药代动力学无显著差异。UGT1A71/*1、*1/*2、*1/*3、*2/3和3/3中MPA从零至12小时的血浆浓度-时间曲线下平均剂量校正面积（AUC0-12）分别为95、98、99、88和86 ng·h/mL/mg（P = 0.9475）。UGT1A9 I399C/C、C/T和T/T中MPA的平均剂量校正AUC0-12分别为87、99和95 ng·h/mL/mg（P = 0.6937）。UGT1A9 I399C/C、C/T和T/T中MPA的剂量校正谷浓度分别为5.4、5.5和4.7 ng/mL/mg（P = 0.5845）。尽管在体外研究时已知UGT1A73和UGT1A9 I399C/C具有低活性变体，但它们在体内的MPA葡萄糖醛酸化活性并未降低。UGT1A7和UGT1A9 I399多态性对MPA药代动力学的个体间差异无影响。
