| Sorafenib is an Inhibitor of UGT1A1 but is Metabolized by UGT1A9: Implications of Genetic Variants on Pharmacokinetics and Hyperbilirubinemia. | |
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MedLine Citation:
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PMID: 22307138 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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PURPOSE: Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)5/6/7 repeat polymorphism in UGT1A1*28. We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration. EXPERIMENTAL DESIGN: Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained using fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients prior to receiving sorafenib (n=41) and 19-30 days following treatment and were compared to UGT1A1*28 genotype. RESULTS: Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC50=18μM; Ki=11.7μM) in vitro. Five patients carrying UGT1A1*28/*28 (n=4) or UGT1A9*3/*3 (n=1) genotypes had first-dose, dose-normalized sorafenib AUCs that were in the 93rd percentile, while three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. DMET genotyping on six patients revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n=12 and n=5; R2=0.38 and R2=0.77; P=0.032 and P=0.051, respectively). UGT1A1*28 carriers demonstrated two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure.CONCLUSIONS: This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib. |
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Authors:
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Cody J Peer; Tristan M Sissung; Aerang Kim; Lokesh Jain; Sukyung Woo; Erin R Gardner; C Tyler Kirkland; Sarah M Troutman; Bevin C English; Emily D Richardson; Joel D Federspiel; David Venzon; Bill Dahut; Elise C Kohn; Shivaani Kummar; Robert Yarchoan; Giuseppe Giaccone; Brigitte C Widemann; William D Figg |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-2-3 |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: - ISSN: 1078-0432 ISO Abbreviation: - Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-2-6 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Clinical Pharmacology Program, National Cancer Institute. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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