Laboratory of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Eur J Clin Pharmacol. 2011 Jan;67(1):39-45. doi: 10.1007/s00228-010-0899-x. Epub 2010 Sep 24.
Ezetimibe is the first lipid-lowering drug that inhibits the intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Ezetimibe is readily absorbed, and undergoes rapid and almost complete glucuronidation by UGT, particularly UGT1A1, in enterocytes during its first pass. Genetic polymorphisms of UGT1A1 may decrease ezetimibe glucuronidation. Therefore, we tested the effects of the UGT1A1*6 and *28 alleles on the pharmacokinetics of ezetimibe.
Three hundred and ninety healthy Korean subjects (347 male and 43 female) were recruited and genotyped for UGT1A1 (*6 and 28 variants). Forty-three subjects among them participated in a pharmacokinetic study of ezetimibe. These 43 subjects were divided into three groups (UGT1A11/1, UGT1A11/X, and UGT1A1X/*X; where *X = *6 or *28) according to the number of UGT1A1 variant alleles. All received a single 10-mg oral dose of ezetimibe. The concentrations of unchanged ezetimibe and ezetimibe-glucuronide in plasma were determined by LC-MS/MS.
The frequencies of the UGT1A1 genotypes were 47.69%, 23.85%, 19.49%, 3.33%, 3.33%, and 2.31% for the *1/*1, *1/*6, *1/*28, *6/*6, *6/*28, and *28/28 genotypes respectively. Besides the C(max) of unchanged ezetimibe, no significant difference was found in any other pharmacokinetic parameter of unchanged ezetimibe or ezetimibe-glucuronide in the three groups. C(max) and AUC(0-48) in subjects with UGT1A128/28 in the UGT1A1X/*X group were significantly different from those in the wild-type.
The UGT1A16 allele was not found to significantly affect the pharmacokinetics of ezetimibe, but the UGT1A128 allele might.
依折麦布是第一种抑制肠道摄取饮食和胆汁中胆固醇的降脂药物，而不影响脂溶性营养素的吸收。依折麦布易被吸收，在首次通过肠细胞时，可迅速且几乎完全被 UGT（尤其 UGT1A1）进行葡萄糖醛酸化。UGT1A1 的遗传多态性可能会降低依折麦布的葡萄糖醛酸化。因此，我们检测了 UGT1A16 和28 等位基因对依折麦布药代动力学的影响。
招募了 390 名健康的韩国受试者（347 名男性和 43 名女性），并对 UGT1A1（6 和28 变异体）进行基因分型。其中 43 名受试者参加了依折麦布的药代动力学研究。根据 UGT1A1 变异等位基因的数量，这 43 名受试者被分为三组（UGT1A1*1/1、UGT1A11/X 和 UGT1A1X/X；其中X=6 或28）。所有受试者均单次口服 10mg 依折麦布。采用 LC-MS/MS 法测定血浆中未改变的依折麦布和依折麦布葡萄糖醛酸化物的浓度。
UGT1A1 基因型的频率分别为 47.69%、23.85%、19.49%、3.33%、3.33%和 2.31%，分别为*1/*1、*1/*6、*1/*28、*6/*6、*6/28 和28/28 基因型。除了未改变的依折麦布的 Cmax 外，三组中未改变的依折麦布或依折麦布葡萄糖醛酸化物的任何其他药代动力学参数均无显著差异。UGT1A1X/X 组中 UGT1A128/*28 受试者的 Cmax 和 AUC（0-48）与野生型相比有显著差异。
未发现 UGT1A16 等位基因对依折麦布的药代动力学有显著影响，但 UGT1A128 等位基因可能有影响。
