Lévesque E, Delage R, Benoit-Biancamano M-O, Caron P, Bernard O, Couture F, Guillemette C
Research Center, CHUL Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
Clin Pharmacol Ther. 2007 Mar;81(3):392-400. doi: 10.1038/sj.clpt.6100073.
We studied whether polymorphisms in the UGT1A8, UGT1A9, and UGT2B7 genes, the enzymes producing the phenolic (MPAG) and acyl (AcMPAG) glucuronides of mycophenolic acid (MPA), could contribute to the interindividual variation observed in mycophenolate mofetil (MMF) pharmacokinetics (PKs). This study enrolled 17 healthy volunteers with no polymorphisms (controls) and 17 carriers of UGT1A9 -275/-2152 selected among 305 individuals genetically screened for UDP-glucuronosyltransferase (UGT) polymorphisms. Additional investigative groups included carriers of UGT1A82 (A173G) (n=9), UGT1A83 (C277Y) (n=4), and UGT1A93 (M33T) (n=5). Genetic analysis also included UGT2B7 to detect UGT2B72 (His268Tyr) and the promoter haplotype -1248A>G, -1241T>C, -1054T>C, -842G>A, -268A>G, -102T>C. Kinetics were measured in plasma and urine after a single 1.5 g oral dose of MMF, by high-performance liquid chromatography coupled with tandem mass spectrometry, over 12 h after drug intake. Compared to controls, MPA exposure was significantly lower for UGT1A9 -275/-2152 carriers, with no significant changes in MPAG. The estimates of enterohepatic (re)cycling (area under the concentration-time curve (AUC6-12 h/AUC0-12 h)) were significantly lower for MPA, MPAG, and AcMPAG in UGT1A9 -275/-2152 subjects. Compared with controls, UGT1A93 carriers had higher MPA and AcMPAG exposure, whereas homozygosity for the UGT1A82 allele and heterozygosity for UGT1A83 allele had no impact on MPA PKs. Compared with UGT2B71/1 individuals (n=10), UGT2B72/*2 subjects (n=17) presented significantly higher free MPA C(max) values and elevated free and total MPA. Results indicate that after a single oral dose of MMF in healthy volunteers, specific UGT genotypes significantly alter MPA PKs and this clearly warrants additional studies with complete and detailed genetic profiling of UGT1A8, UGT1A9, and UGT2B7 genes.
我们研究了参与生成霉酚酸（MPA）的酚类（MPAG）和酰基（AcMPAG）葡糖醛酸苷的UGT1A8、UGT1A9和UGT2B7基因中的多态性是否会导致在霉酚酸酯（MMF）药代动力学（PKs）中观察到的个体间差异。本研究招募了17名无多态性的健康志愿者（对照组）以及从305名经基因筛查的UDP - 葡糖醛酸基转移酶（UGT）多态性个体中挑选出的17名UGT1A9 -275/-2152携带者。其他研究组包括UGT1A82（A173G）携带者（n = 9）、UGT1A83（C277Y）携带者（n = 4）和UGT1A93（M33T）携带者（n = 5）。基因分析还包括UGT2B7，以检测UGT2B72（His268Tyr）以及启动子单倍型 -1248A>G、-1241T>C、-1054T>C、-842G>A、-268A>G、-102T>C。在单次口服1.5 g MMF后，通过高效液相色谱 - 串联质谱法在服药后12小时内测量血浆和尿液中的动力学。与对照组相比，UGT1A9 -275/-
