Zhang Wei-Xia, Chen Guo-Lin, Zhang Wei, Tan Zhi-Rong, Liu Jie, Zhou Gan, Hu Dong-Li, Zhou Hong-Hao
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan 410078, China.
Clin Chim Acta. 2005 Sep;359(1-2):46-52. doi: 10.1016/j.cccn.2005.03.010.
We investigated the linkage between SNPs in exon 12 (C1236T), exon 21 (G2677T/A) and exon 26 (C3435T) of MDR1, and explored the effect of linked polymorphism on the absorption of talinolol after a single oral dose of 100 mg.
The genotype of 192 healthy Chinese volunteers was determined using PCR-RFLP with respect to the MDR1 alleles of interest, C1236T, G2677T/A and C3435T. Linkage disequilibrium was analyzed using PHASE software. Consecutive eligible subjects received a single oral dose of 100 mg talinolol. Venous blood samples were taken at intervals up to 60 h post dose for HPLC analysis of plasma concentration of talinolol to obtain a pharmacokinetic profile.
Linkage disequilibrium existed between exon 21 (G2677T/A) and exon 26 (C3435T), exon 12 (C1236T) and exon 21 (G2677T/A), but not between exon 12 (C1236T) and exon 21 (G2677T/A). AUC (0,3 h), AUC (0, infinity), Cmax and Cmax/AUC (0, infinity), used as indices of talinolol absorption, were not significantly different between the genotype groups of 2677GG/3435TT, 2677TT/3435TT, 2677GT/3435CT and 2677AT/3435CT. For these 4 groups, AUC(0,3 h) were 436.8 +/- 50.1, 510.1 +/- 86.3, 466.1 +/- 77.8 and 437.2 +/- 73.4 (microg x h/l) and the Cmax/AUC (0, infinity) were 0.097 +/- 0.018, 0.093 +/- 0.022, 0.105 +/- 0.014 and 0.102 +/- 0.027 (h(-1)), respectively. (P > 0.05).
The linked MDR1 polymorphisms in exon 21 G2677T/A and exon 26 C3435T apparently did not contribute to the absorptive pharmacokinetics of a single oral dose of 100 mg talinolol.
我们研究了多药耐药基因1（MDR1）第12外显子（C1236T）、第21外显子（G2677T/A）和第26外显子（C3435T）中的单核苷酸多态性（SNP）之间的连锁关系，并探讨了连锁多态性对单次口服100 mg他林洛尔吸收的影响。
采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法，对192名健康中国志愿者的感兴趣的MDR1等位基因C1236T、G2677T/A和C3435T进行基因分型。使用PHASE软件分析连锁不平衡。连续符合条件的受试者单次口服100 mg他林洛尔。在给药后长达60小时的时间间隔内采集静脉血样，通过高效液相色谱法（HPLC）分析血浆他林洛尔浓度，以获得药代动力学曲线。
第21外显子（G2677T/A）和第26外显子（C3435T）之间、第12外显子（C1236T）和第21外显子（G2677T/A）之间存在连锁不平衡，但第12外显子（C1236T）和第26外显子（C3435T）之间不存在连锁不平衡。作为他林洛尔吸收指标的0至3小时血药浓度-时间曲线下面积（AUC(0,3 h)）、0至无穷大血药浓度-时间曲线下面积（AUC(0, infinity)）、血药峰浓度（Cmax）以及Cmax/AUC(0, infinity)，在2677GG/3435TT、2677TT/3435TT、2677GT/3435CT和2677AT/3435CT基因型组之间无显著差异。对于这4组，AUC(0,3 h)分别为436.8±50.1、510.1±86.3、466.1±77.8和437.2±73.4（μg·h/L），Cmax/AUC(0, infinity)分别为0.097±0.018、0.093±0.022、0.105±0.014和0.102±0.027（h⁻¹）。（P>0.05）。
第21外显子G2677T/A和第26外显子C3435T中连锁的MDR1多态性显然对单次口服100 mg他林洛尔的吸收药代动力学没有影响。
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