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Effects of UDP-glucuronosyltransferase polymorphisms on the pharmacokinetics of ezetimibe in healthy subjects

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

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.

Methods

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 (UGT1A1*1/*1, UGT1A1*1/*X, and UGT1A1*X/*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.

Results

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 Cmax of unchanged ezetimibe, no significant difference was found in any other pharmacokinetic parameter of unchanged ezetimibe or ezetimibe–glucuronide in the three groups. Cmax and AUC0–48 in subjects with UGT1A1*28/*28 in the UGT1A1*X/*X group were significantly different from those in the wild-type.

Conclusions

The UGT1A1*6 allele was not found to significantly affect the pharmacokinetics of ezetimibe, but the UGT1A1*28 allele might.

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Abbreviations

UGT1A1:

UDP-glucuronosyltransferases 1A1

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Conflict of interest

The authors declare that they have no conflict of interest.

Funding

This study was supported by the Samsung Research Fund at Sungkyunkwan University, 2007.

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Authors and Affiliations

  1. Laboratory of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea

    Jung-Woo Bae, Chang-Ik Choi, Jin-Hee Lee, Choon-Gon Jang & Seok-Yong Lee

  2. National Institute of Food and Drug Safety Evaluation, Korean Food Drug Administration, Seoul, 122-704, Republic of Korea

    Myeon-Woo Chung

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  1. Jung-Woo Bae
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Correspondence to Seok-Yong Lee.

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Bae, JW., Choi, CI., Lee, JH. et al. Effects of UDP-glucuronosyltransferase polymorphisms on the pharmacokinetics of ezetimibe in healthy subjects. Eur J Clin Pharmacol 67, 39–45 (2011). https://doi.org/10.1007/s00228-010-0899-x

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  • DOI: https://doi.org/10.1007/s00228-010-0899-x

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