Metabolite Identification of a Novel Anti-Leishmanial Agent OJT007 in Rat Liver Microsomes Using LC-MS/MS

Maria Eugenia Rincon Nigro; Ting Du; Song Gao; Manvir Kaur; Huan Xie; Omonike Arike Olaleye; Dong Liang

doi:10.3390/molecules27092854

Metabolite Identification of a Novel Anti-Leishmanial Agent OJT007 in Rat Liver Microsomes Using LC-MS/MS

Maria Eugenia Rincon Nigro, Ting Du, Song Gao, Manvir Kaur, Huan Xie, Omonike Arike Olaleye, Dong Liang

Houston Methodist

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

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.

Original language	English (US)
Article number	2854
Journal	Molecules
Volume	27
Issue number	9
DOIs	https://doi.org/10.3390/molecules27092854
State	Published - Apr 30 2022

Keywords

CYP450
LC-MS/MS
UGT
liver microsomes
metabolic stability
Glucuronidase/metabolism
Rats
Microsomes/metabolism
Tandem Mass Spectrometry
Animals
Microsomes, Liver/metabolism
Chromatography, Liquid
Glucuronides/pharmacology

ASJC Scopus subject areas

Drug Discovery
Analytical Chemistry
Chemistry (miscellaneous)
Molecular Medicine
Physical and Theoretical Chemistry
Pharmaceutical Science
Organic Chemistry

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10.3390/molecules27092854

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title = "Metabolite Identification of a Novel Anti-Leishmanial Agent OJT007 in Rat Liver Microsomes Using LC-MS/MS",

abstract = "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{\textquoteright}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.",

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author = "Nigro, {Maria Eugenia Rincon} and Ting Du and Song Gao and Manvir Kaur and Huan Xie and Olaleye, {Omonike Arike} and Dong Liang",

note = "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: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

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language = "English (US)",

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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.

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KW - Microsomes/metabolism

KW - Tandem Mass Spectrometry

KW - Animals

KW - Microsomes, Liver/metabolism

KW - Chromatography, Liquid

KW - Glucuronides/pharmacology

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Metabolite Identification of a Novel Anti-Leishmanial Agent OJT007 in Rat Liver Microsomes Using LC-MS/MS

Abstract

Keywords

ASJC Scopus subject areas

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