MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine
MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine
复制标题
DOI：
10.1046/j.1365-2125.2002.01591.x
复制
发表时间：
2002-05-01
影响因子：
3.4
通讯作者：
Fromm, MF
中科院分区：
文献类型：
--
作者：
Drescher, S;Schaeffeler, E;Fromm, MF
目的 人 MDR1 基因中的 C3435T 多态性与肠道 P-糖蛋白表达降低、外周血细胞蛋白功能降低以及 P-糖蛋白底物地高辛血浆浓度升高相关。使用非索非那定（一种已知的 P-糖蛋白底物），检验了该假设是否也影响人类中其他药物的处置。 方法 10 位 3435 位（CC）野生型等位基因纯合的白人受试者和 10 位 3435 位 T 纯合的个体参与了这项研究。单次口服 180 mg 盐酸非索非那定。使用灵敏的 LC/MS 方法测量非索非那定的血浆和尿液浓度长达 72 小时。此外，利用CD56(+)细胞中P-糖蛋白底物罗丹明123的流出来评估P-糖蛋白功能。结果非索非那定血浆浓度在研究人群中差异很大。然而，CC 组和 TT 组之间的非索非那定分布没有显着差异（例如 AUC（0，无穷大）CC 与 TT：3567.1+/-1535.5 与 3910.1+/-1894.8 ng ml(-1) h，NS；差异的 95% CI -1364.9、2050.9）。相反，与CC组相比，TT组CD56(+)细胞中P-糖蛋白功能显着降低（罗丹明荧光CC vs TT：45.6+/-7.2% vs 61.1+/-12.3%，P
Aims The C3435T polymorphism in the human MDR1 gene is associated with lower intestinal P-glycoprotein expression, reduced protein function in peripheral blood cells and higher plasma concentrations of the P-glycoprotein substrate digoxin. Using fexofenadine, a known P-glycoprotein substrate, the hypothesis was tested whether this polymorphism also affects the disposition of other drugs in humans.Methods Ten Caucasian subjects homozygous for the wild-type allele at position 3435 (CC) and 10 individuals homozygous for T at position 3435 participated in this study. A single oral dose of 180 mg fexofenadine HCl was administered. Plasma and urine concentrations of fexofenadine were measured up to 72 h using a sensitive LC/MS method. In addition, P-glycoprotein function was assessed using efflux of the P-glycoprotein substrate rhodamine 123 from CD56(+) cells.Results Fexofenadine plasma concentrations varied considerably among the study population. However, fexofenadine disposition was not significantly different between the CC and TT groups (e.g. AUC(0,infinity) CC vs TT: 3567.1+/-1535.5 vs 3910.1+/-1894.8 ng ml(-1) h, NS; 95% CI on the difference -1364.9, 2050.9). In contrast, P-glycoprotein function was significantly decreased in CD56(+) cells of the TT compared with the CC group (rhodamine fluorescence CC vs TT: 45.6+/-7.2% vs 61.1+/-12.3%, P