Influence of drug transporters and UGT polymorphisms on pharmacokinetics of phenolic glucuronide metabolite of mycophenolic acid in Japanese renal transplant recipients
Influence of drug transporters and UGT polymorphisms on pharmacokinetics of phenolic glucuronide metabolite of mycophenolic acid in Japanese renal transplant recipients
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DOI：
10.1097/ftd.0b013e3181838063
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发表时间：
2008-10-01
影响因子：
2.5
通讯作者：
Suzuki, Toshio
中科院分区：
文献类型：
--
作者：
Miura, Masatomo;Kagaya, Hideaki;Suzuki, Toshio
霉酚酸（NMA）主要通过尿苷二磷酸-葡萄糖醛酸转移酶（UGTs）转化为酚类MPA葡萄糖醛酸（MPAG）。MPAG通过有机阴离子转运多肽（基因SLCO）、多药耐药蛋白2（基因ABCC2）、乳腺癌耐药蛋白（BCRP，基因ABCG2）或p糖蛋白（基因ARM）等转运体排出体外。本研究调查了80名日本肾移植受者UGTs、SLCOs、ABCB1、ABCC2和ABCG2多态性与MPAG药代动力学的关系。80名受者在指定时间（0900和2100）每12小时给予由霉酚酸酯和他克莫司组成的联合免疫抑制治疗重复剂量。肾移植后第28天，采用高效液相色谱法测定血浆中MPA和MPAG的浓度。UGT1A1、UGT1A6、UGT1A7、UGT1A8和ugt1a9i399c /T基因型之间MPAG/MPA的血浆浓度-时间曲线（AUC）比值下面积无显著差异。另一方面，SLCO1B1中位剂量调整的MPAG AUC，12 1a/1a+1a/1b+1b+1b +1b+1b （n = 53）和1a/*15 +1b /*15+*15/*15 （n = 27）分别为1549和1134 mg.h L-1 g(-1)（多因素分析P = 0.03004）。SLCO1B3 334T/T+T/G （699G/G+G/A, n = 46）和334G/G （699A/A, n = 34）中位剂量调整AUC（0-12）分别为1191和1580 mg.h L-1 G(-1)（多因素分析P = 0.02792）。ABCB1 C3435T和ABCC2 C-24T基因型之间MPAG的剂量调整AUC（0-12）无显著差异。然而，ABCG2 421C/A+A/A组（n = 44） MPAG剂量调整AUC（0-12）明显低于C/C组（n = 36） （P = 0.0295）。总之，我们的研究结果表明，MPAG的药代动力学受SLCO1B1和SLCO1B3多态性的显著影响，而不受UGT多态性的影响。BCRP而非多药耐药蛋白2似乎是与MPAG胆道排泄相关的转运蛋白。
Mycophenolic acid (NMA) is mainly glucuronized by uridine diphosphate-glucuronosyltransferases (UGTs) into the phenolic MPA glucuronide (MPAG). MPAG is excreted by transporters such as organic anion-transporting polypeptide (gene SLCO), multidrug resistance protein 2 (gene ABCC2), breast cancer resistance protein (BCRP, gene ABCG2) or P-glycoprotein (gene ARM). This study investigated the association of UGTs, SLCOs, ABCB1, ABCC2, and ABCG2 polymorphisms with MPAG pharmacokinetics in 80 Japanese 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 (0900 and 2 100). On day 28, after renal transplantation, plasma concentrations of MPA and MPAG were measured by high-performance liquid chromatography There were no significant differences in the area under the plasma concentration-time curve (AUC) ratio of MPAG/MPA between UGT1A1, UGT1A6, UGT1A7, UGT1A8, and UGT1A9 I399C/T genotypes. On the other hand, the median dose-adjusted AUC,12 of MPAG in SLCO1B1 1a/1a+1a/1b+1b+1b (n = 53) and 1a/*15 + 1b/*15+*15/*15 (n = 27) were 1549 and 1134 mg.h L-1 g(-1), respectively (P = 0.03004 in multivariate analysis). The median dose-adjusted AUC(0-12) of MPAG in SLCO1B3 334T/T+T/G (699G/G+G/A, n = 46)and 334G/G (699A/A, n = 34) was 1191 and 1580 mg.h L-1 g(-1), respectively (P = 0.02792 in multivariate analysis). There were no significant differences in the dose-adjusted AUC(0-12) of MPAG between the ABCB1 C3435T and ABCC2 C-24T genotypes. However, the dose-adjusted AUC(0-12) of MPAG was significantly lower in recipients with ABCG2 421C/A+A/A (n = 44) than in those with C/C (n = 36) (P = 0.0295). In conclusion, our findings showed that MPAG pharmacokinetics were significantly influenced by SLCO1B1 and SLCO1B3 polymorphisnis and not by UGT polymorphisms. BCRP rather than multidrug resistance protein 2 seems to be the transporter associated with biliary excretion of MPAG.