Sawyer Michael B, Innocenti Federico, Das Soma, Cheng Cheng, Ramírez Jacqueline, Pantle-Fisher Friedl H, Wright Constance, Badner Judith, Pei Deqing, Boyett James M, Cook Edwin, Ratain Mark J
Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL, USA.
Clin Pharmacol Ther. 2003 Jun;73(6):566-74. doi: 10.1016/S0009-9236(03)00053-5.
We investigated the variation in the uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) gene in patients receiving patient-controlled analgesia with morphine. UGT2B7 was sequenced in phenotypic extremes (n = 12) of the distribution of morphine-6-glucuronide/morphine plasma ratios. A new -161C/T promoter variant was in complete linkage disequilibrium with the 802C/T variant and was more frequent in low glucuronidators (P =.039). Both variants were genotyped in all patients (n = 86), and complete linkage disequilibrium was confirmed. Trend analysis showed reduced morphine-6-glucuronide/morphine ratios in patients with T/T, C/T, and C/C genotypes (T/T > C/T > C/C) (P =.031). Morphine levels were lower in T/T patients (median, 18 ng/mL [range, 18-1490 ng/mL]) as compared with C/T and C/C patients combined (median, 66 ng/m; range, 18-3995 ng/mL) (P =.04). Morphine-6-glucuronide and morphine-3-glucuronide concentrations were significantly lower in C/C patients (median, 18 ng/mL; range, 0-66 ng/mL; and median, 152 ng/mL; range, 30-434 ng/mL; respectively) compared with C/T and T/T patients combined (median, 43 ng/mL; range, 0-193 ng/mL; and median, 242 ng/mL; range, 33-1381 ng/mL; respectively) (P =.045 and P =.004, respectively). Interindividual differences in morphine glucuronidation may be the result of genetic variation in UGT2B7, and further studies are indicated.
我们研究了接受吗啡患者自控镇痛的患者中尿苷二磷酸葡萄糖醛酸基转移酶2B7（UGT2B7）基因的变异情况。对吗啡-6-葡萄糖醛酸/吗啡血浆比值分布的表型极端情况（n = 12）中的UGT2B7进行了测序。一种新的-161C/T启动子变异与802C/T变异完全连锁不平衡，且在低葡萄糖醛酸化者中更常见（P = 0.039）。对所有患者（n = 86）进行了这两种变异的基因分型，并证实了完全连锁不平衡。趋势分析显示，T/T、C/T和C/C基因型患者（T/T > C/T > C/C）的吗啡-6-葡萄糖醛酸/吗啡比值降低（P = 0.031）。与C/T和C/C患者合并组（中位数，66 ng/m；范围，18 - 3995 ng/mL）相比，T/T患者的吗啡水平较低（中位数，18 ng/mL [范围，18 - 1490 ng/mL]）（P = 0.04）。与C/T和T/T患者合并组（中位数，43 ng/mL；范围，0 - 193 ng/mL；和中位数，242 ng/mL；范围，33 - 1381 ng/mL）相比，C/C患者的吗啡-6-葡萄糖醛酸和吗啡-3-葡萄糖醛酸浓度显著较低（分别为中位数，18 ng/mL；范围，0 - 66 ng/mL；和中位数，152 ng/mL；范围，30 - 434 ng/mL）（分别为P = 0.045和P = 0.004）。吗啡葡萄糖醛酸化的个体差异可能是UGT2B7基因变异的结果，需要进一步研究。
