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Research ArticleArticle

Glucuronidation of OTS167 in Humans Is Catalyzed by UDP-Glucuronosyltransferases UGT1A1, UGT1A3, UGT1A8, and UGT1A10

Jacqueline Ramírez, Snezana Mirkov, Larry K. House and Mark J. Ratain
Drug Metabolism and Disposition July 2015, 43 (7) 928-935; DOI: https://doi.org/10.1124/dmd.115.063271
Jacqueline Ramírez
Department of Medicine, University of Chicago, Chicago, Illinois
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Snezana Mirkov
Department of Medicine, University of Chicago, Chicago, Illinois
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Larry K. House
Department of Medicine, University of Chicago, Chicago, Illinois
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Mark J. Ratain
Department of Medicine, University of Chicago, Chicago, Illinois
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Abstract

OTS167 is a potent maternal embryonic leucine zipper kinase inhibitor undergoing clinical testing as antineoplastic agent. We aimed to identify the UDP-glucuronosyltransferases (UGTs) involved in OTS167 metabolism, study the relationship between UGT genetic polymorphisms and hepatic OTS167 glucuronidation, and investigate the inhibitory potential of OTS167 on UGTs. Formation of a single OTS167-glucuronide (OTS167-G) was observed in pooled human liver (HLM) (Km = 3.4 ± 0.2 µM), intestinal microsomes (HIM) (Km = 1.7 ± 0.1 µM), and UGTs. UGT1A1 (64 µl/min/mg) and UGT1A8 (72 µl/min/mg) exhibited the highest intrinsic clearances (CLint) for OTS167, followed by UGT1A3 (51 µl/min/mg) and UGT1A10 (47 µl/min/mg); UGT1A9 was a minor contributor. OTS167 glucuronidation in HLM was highly correlated with thyroxine glucuronidation (r = 0.91, P < 0.0001), SN-38 glucuronidation (r = 0.79, P < 0.0001), and UGT1A1 mRNA (r = 0.72, P < 0.0001). Nilotinib (UGT1A1 inhibitor) and emodin (UGT1A8 and UGT1A10 inhibitor) exhibited the highest inhibitory effects on OTS167-G formation in HLM (68%) and HIM (47%). We hypothesize that OTS167-G is an N-glucuronide according to mass spectrometry. A significant association was found between rs6706232 and reduced OTS167-G formation (P = 0.03). No or weak UGT inhibition (range: 0–21%) was observed using clinically relevant OTS167 concentrations (0.4–2 µM). We conclude that UGT1A1 and UGT1A3 are the main UGTs responsible for hepatic formation of OTS167-G. Intestinal UGT1A1, UGT1A8, and UGT1A10 may contribute to first-pass OTS167 metabolism after oral administration.

Footnotes

    • Received January 8, 2015.
    • Accepted April 13, 2015.
  • This work was supported by OncoTherapy Science (Kawasaki City, Kanagawa, Japan) and the National Institutes of Health National Institute of General Medical Sciences [Grant U01GM061393 to Pharmacogenomics of Anticancer Agents Research Group].

  • This work was previously presented as preliminary data in a poster session at the following meeting: 115th Annual Meeting of American Society for Clinical Pharmacology and Therapeutics; March 18-22, 2014; Atlanta, GA [Ramirez J, Mirkov S, Matsuo Y, Ratain MJ. In vitro glucuronidation of OTS167. Clin Pharmacol Ther, 95:S73, abstract no. PII-037].

  • dx.doi.org/10.1124/dmd.115.063271.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (7)
Drug Metabolism and Disposition
Vol. 43, Issue 7
1 Jul 2015
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Research ArticleArticle

In Vitro Glucuronidation of OTS167

Jacqueline Ramírez, Snezana Mirkov, Larry K. House and Mark J. Ratain
Drug Metabolism and Disposition July 1, 2015, 43 (7) 928-935; DOI: https://doi.org/10.1124/dmd.115.063271

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Research ArticleArticle

In Vitro Glucuronidation of OTS167

Jacqueline Ramírez, Snezana Mirkov, Larry K. House and Mark J. Ratain
Drug Metabolism and Disposition July 1, 2015, 43 (7) 928-935; DOI: https://doi.org/10.1124/dmd.115.063271
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