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Cancer Prevention Research
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Research Article

Characterization of Raloxifene Glucuronidation: Potential Role of UGT1A8 Genotype on Raloxifene Metabolism In Vivo

Dongxiao Sun, Nathan R Jones, Andrea Manni and Philip Lazarus
Dongxiao Sun
Departments of 1Pharmacology and 2Medicine, Pennsylvania State College of Medicine, Hershey, Pennsylvania; and 3Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington
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Nathan R Jones
Departments of 1Pharmacology and 2Medicine, Pennsylvania State College of Medicine, Hershey, Pennsylvania; and 3Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington
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Andrea Manni
Departments of 1Pharmacology and 2Medicine, Pennsylvania State College of Medicine, Hershey, Pennsylvania; and 3Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington
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Philip Lazarus
Departments of 1Pharmacology and 2Medicine, Pennsylvania State College of Medicine, Hershey, Pennsylvania; and 3Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington
Departments of 1Pharmacology and 2Medicine, Pennsylvania State College of Medicine, Hershey, Pennsylvania; and 3Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington
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DOI: 10.1158/1940-6207.CAPR-12-0448 Published July 2013
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Abstract

Raloxifene is a second-generation selective estrogen receptor modulator used for the prevention and treatment of osteoporosis and the prevention of breast cancer in postmenopausal women. Raloxifene is extensively metabolized by glucuronidation to form raloxifene-6-glucuronide (ral-6-Gluc) and raloxifene-4′-glucuronide (ral-4′-Gluc). The goal of the present study was to determine whether functional polymorphisms in active UGTs could play a role in altered raloxifene glucuronidation in vivo. Using homogenates from HEK293 UGT-overexpressing cell lines, raloxifene was shown to be glucuronidated primarily by the hepatic UGTs 1A1 and 1A9 and the extra-hepatic UGTs 1A8 and 1A10; no detectable raloxifene glucuronidation activity was found for UGT2B enzymes. Functional UGT1A1 transcriptional promoter genotypes were significantly (Ptrend = 0.005) associated with ral-6-Gluc formation in human liver microsomes, and, consistent with the decreased raloxifene glucuronidation activities observed in vitro with cell lines overexpressing UGT1A8 variants, the UGT1A8*2 variant was significantly (P = 0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-4′-Gluc exhibited 1:100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised about 99% of the circulating raloxifene dose in raloxifene-treated subjects, with ral-4′-Gluc comprising ∼70% of raloxifene glucuronides. Plasma ral-6-Gluc (Ptrend = 0.0025), ral-4′-Gluc (Ptrend = 0.001), and total raloxifene glucuronides (Ptrend = 0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] versus intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] versus fast metabolizers [UGT1A8 (*2/*2). These data suggest that raloxifene metabolism may be dependent on UGT1A8 genotype and that UGT1A8 genotype may play an important role in overall response to raloxifene. Cancer Prev Res; 6(7); 719–30. ©2013 AACR.

  • Received November 14, 2012.
  • Revision received March 5, 2013.
  • Accepted May 3, 2013.
  • ©2013 American Association for Cancer Research.
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Cancer Prevention Research: 6 (7)
July 2013
Volume 6, Issue 7
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Characterization of Raloxifene Glucuronidation: Potential Role of UGT1A8 Genotype on Raloxifene Metabolism In Vivo
Dongxiao Sun, Nathan R Jones, Andrea Manni and Philip Lazarus
Cancer Prev Res July 1 2013 (6) (7) 719-730; DOI: 10.1158/1940-6207.CAPR-12-0448

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Characterization of Raloxifene Glucuronidation: Potential Role of UGT1A8 Genotype on Raloxifene Metabolism In Vivo
Dongxiao Sun, Nathan R Jones, Andrea Manni and Philip Lazarus
Cancer Prev Res July 1 2013 (6) (7) 719-730; DOI: 10.1158/1940-6207.CAPR-12-0448
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