Contribution of polymorphisms in UDP-glucuronosyltransferase and CYP2D6 to the individual variation in disposition of carvedilol.
Contribution of polymorphisms in UDP-glucuronosyltransferase and CYP2D6 to the individual variation in disposition of carvedilol.
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发表时间：
2006
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通讯作者：
Y. Takekuma;T. Takenaka;M. Kiyokawa;Koujiro Yamazaki;H. Okamoto;A. Kitabatake;H. Tsutsui;M. Sugawara
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作者：
Y. Takekuma;T. Takenaka;M. Kiyokawa;Koujiro Yamazaki;H. Okamoto;A. Kitabatake;H. Tsutsui;M. Sugawara
卡维地洛具有β-肾上腺素能阻滞和血管舒张作用，主要经尿苷二磷酸葡萄糖醛酸转移酶（UGT）1A1、UGT 2B4、UGT 2B7和CYP 2D6代谢。本研究的目的是确定葡萄糖醛酸化的活性是否对卡维地洛的曲线下面积（AUC）有影响，以及UGT和CYP 2D6的多态性是否有助于日本人卡维地洛处置的个体差异。方法采用反相高效液相色谱法测定卡维地洛及其葡萄糖醛酸苷的血药浓度。采用直接测序法对UGT 1A1、UGT 2B4和UGT 2B7基因进行基因分型。使用扩增难治性突变系统（ARMS）试验和PCR-限制性片段长度多态性（RFLP）进行CYP2D6基因分型。结果高AUC组卡维地洛葡萄糖醛酸化能力明显低于低AUC组。葡萄糖醛酸化能力低组UGT 1A1 * 6、UGT 2B7 * 3和CYP 2D6 * 10频率显著高于葡萄糖醛酸化能力高组，CYP 2D6 * 5频率也有相同趋势，但差异无统计学意义。结论UGT 1A1、UGT 2B7和CYP 2D6基因多态性对卡维地洛在日本人体内的药代动力学和处置有显著影响。
PURPOSE It has been reported that carvedilol, which has beta-adrenergic blocking and vasodilating activities, is mainly metabolized by UDP-glucuronosyltransferase (UGT) 1A1, UGT2B4, UGT2B7 and CYP2D6. The aim of this study was to determine whether the activity of glucuronidation has an influence on the area under the curve (AUC) of carvedilol and whether polymorphisms in UGTs and CYP2D6 contribute to individual variation in disposition of carvedilol in Japanese. METHODS Plasma concentrations of carvedilol and its glucuronide were determined by reversed-phase high-performance liquid chromatography (HPLC). Genotyping of UGT1A1, UGT2B4 and UGT2B7 genes was carried out by the direct sequence method. CYP2D6 genotyping was carried out using an amplification refractory mutation system (ARMS) assay and PCR-restriction fragment length polymorphism (RFLP). RESULTS The level of carvedilol glucuronidation ability in the high-level AUC group was significantly lower than that in the low-level group. The frequencies of UGT1A1*6, UGT2B7*3 and CYP2D6*10 in the low level ability of glucuronidation group were significantly higher than those in the high level group, and the same tendency was found in the frequency of CYP2D6*5, though there was no significant difference. CONCLUSION Polymorphisms of UGT1A1, UGT2B7 and CYP2D6 strongly affect the pharmacokinetics and disposition of carvedilol in Japanese.