TY - JOUR
T1 - Metabolite Identification of a Novel Anti-Leishmanial Agent OJT007 in Rat Liver Microsomes Using LC-MS/MS
AU - Nigro, Maria Eugenia Rincon
AU - Du, Ting
AU - Gao, Song
AU - Kaur, Manvir
AU - Xie, Huan
AU - Olaleye, Omonike Arike
AU - Liang, Dong
N1 - Funding Information:
Funding: This work was supported in part by the Center for Biomedical and Minority Health Research (CBMHR), National Institute of Health (NIH), grant U54MD007605, and the Cancer Prevention and Research Institute of Texas, grant RP180748.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/4/30
Y1 - 2022/4/30
N2 - The purpose of this study was to identify potential metabolic pathways and metabolites of OJT007, a methionine aminopeptidase 1 (MetAP1) inhibitor. OJT007 is a novel drug with potent antiproliferative effects against Leishmania Major. We conducted in vitro Phase I oxidation and Phase II glucuronidation assays on OJT007 using rat liver microsomes. Four unknown metabolites were initially identified using a UPLC-UV system from microsomal incubated samples. LC-MS/MS analysis was then used to identify the structural characteristics of these metabolites via precursor ion scan, neutral loss scan, and product ion scan. A glucuronide metabolite was further confirmed by β-glucuronidase hydrolysis. The kinetic parameters of OJT007 glucuronidation demonstrated that OJT007 undergoes rapid metabolism. These results demonstrate the liver’s microsomal ability to mediate three mono-oxidated metabolites and one mono-glucuronide metabolite. This suggests hepatic glucuronidation metabolism of OJT007 may be the cause of its poor oral bioavailability.
AB - The purpose of this study was to identify potential metabolic pathways and metabolites of OJT007, a methionine aminopeptidase 1 (MetAP1) inhibitor. OJT007 is a novel drug with potent antiproliferative effects against Leishmania Major. We conducted in vitro Phase I oxidation and Phase II glucuronidation assays on OJT007 using rat liver microsomes. Four unknown metabolites were initially identified using a UPLC-UV system from microsomal incubated samples. LC-MS/MS analysis was then used to identify the structural characteristics of these metabolites via precursor ion scan, neutral loss scan, and product ion scan. A glucuronide metabolite was further confirmed by β-glucuronidase hydrolysis. The kinetic parameters of OJT007 glucuronidation demonstrated that OJT007 undergoes rapid metabolism. These results demonstrate the liver’s microsomal ability to mediate three mono-oxidated metabolites and one mono-glucuronide metabolite. This suggests hepatic glucuronidation metabolism of OJT007 may be the cause of its poor oral bioavailability.
KW - CYP450
KW - LC-MS/MS
KW - UGT
KW - liver microsomes
KW - metabolic stability
KW - Glucuronidase/metabolism
KW - Rats
KW - Microsomes/metabolism
KW - Tandem Mass Spectrometry
KW - Animals
KW - Microsomes, Liver/metabolism
KW - Chromatography, Liquid
KW - Glucuronides/pharmacology
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U2 - 10.3390/molecules27092854
DO - 10.3390/molecules27092854
M3 - Article
C2 - 35566205
AN - SCOPUS:85129816360
VL - 27
JO - Molecules (Basel, Switzerland)
JF - Molecules (Basel, Switzerland)
SN - 1420-3049
IS - 9
M1 - 2854
ER -