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Identification of a novel, in vitro O‐glucuronide metabolite of a MEK inhibitor, AR00340509, linked by way of a carbonyl oxygen
Author(s) -
Franklin Ronald Brian,
Allen Andrew,
Kraser Christopher F,
Dinkel Victoria L.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb625
Subject(s) - chemistry , metabolite , glucuronide , moiety , stereochemistry , amide , microsome , tautomer , metabolism , in vitro , biochemistry
While studying the metabolism of unique MEK inhibitors, including AR00340509 (4‐((4‐bromo‐2‐fluorophenyl)amino)‐N‐(2‐hydroxyethoxy)‐1,5‐dimethyl‐6‐oxo‐1,6‐dihydropyridine‐3‐carboxamide), we identified a novel O‐glucuronide linked through the carbonyl oxygen of the hydroxamate moiety. This glucuronide metabolite was observed in UDPGA‐supplemented hepatic microsomes and hepatocytes from a number of animal species including humans and was formed by rUGT1A1 and rUGT1A3. The terminal O‐linked glucuronide on the hydroxamate terminal OH side chain and N‐glucuronide of the amide metabolite were observed. The identity of the O‐linked carbonyl glucuronide metabolite was supported by the synthesis of the peracetate derivative of the glucuronide. Within this structural class of MEK inhibitors, some but not all, of the O‐linked carbonyl glucuronides were unstable and identification of the pathway was carried out via the more stable peracetate. Accurate mass determination of the peracetylated glucuronide of AR00340509 was carried with LC‐QTOF instrumentation, which yielded an M+H ion of 730.1258 and a structural formula of C 29 H 34 Br F N 3 O 13 . The structural class of MEK inhibitors studied lend themselves to enhanced tautomer enolization, thereby facilitating the formation of these unique O‐glucuronides. We are investigating factors affecting the formation of carbonyl glucuronides, including substitutions with both electron withdrawing and electron donating entities.