Metabolite profiling of praziquantel and its analogs during the analysis of in vitro metabolic stability using information-dependent acquisition on a hybrid triple quadrupole linear ion trap mass spectrometer

Jiangeng Huang, Sai Praneeth R. Bathena, Yazen Alnouti

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Rapid determination of in vitro metabolic stability and metabolite profiling of new chemical entities using microsomes or other liver preparations is one of the most important steps in drug discovery. In this paper, we report the use of liquid chromatography-hybrid triple quadrupole/linear ion trap mass spectrometry for the simultaneous analysis of metabolic stability, metabolite profiling, and the kinetics of metabolite formation of praziquantel and three structural analogs. Multiple reaction monitoring (MRM) scans were used to quantify the disappearance of parent compounds and the formation of metabolites. MRM-information dependent acquisition-enhanced product ion (MRM-IDA-EPI) scans were used for the identification of the metabolites formed. Metabolic stability of these anthelmintics were studied in human liver microsomes (HLM) using MRM as a survey scan, which resulted in the identification of a higher number of metabolites compared to neutral loss (NL), precursor ion (PI), and enhanced mass spectrometry (EMS) scans. MRM-IDA-EPI scans resulted in the generation of similar calibration curves to MRM-only quantitative analysis. Therefore, the quantitative capabilities of the method was not affected by the additional qualitative information obtained during the same run. The formation of major metabolites was also simultaneously monitored, which could be used to understand the kinetics and mechanism of metabolite formation. Finally, our data demonstrate that the three analogs had higher metabolic stability than the anthelmintic prototype (praziquantel).

Original languageEnglish (US)
Pages (from-to)487-499
Number of pages13
JournalDrug Metabolism and Pharmacokinetics
Volume25
Issue number5
DOIs
StatePublished - Jan 1 2010

Fingerprint

Praziquantel
Anthelmintics
Ions
Mass Spectrometry
Liver Microsomes
Drug Discovery
Microsomes
Liquid Chromatography
Calibration
Liver
In Vitro Techniques

Keywords

  • Information-dependent acquisition
  • Metabolic stability
  • Metabolite profiling
  • Praziquantel
  • Structural analogs
  • Tandem mass spectrometry
  • Ultra-performance liquid chromatography

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

Cite this

@article{10d57d52e3bf410f9c4a4b47c285a4ee,
title = "Metabolite profiling of praziquantel and its analogs during the analysis of in vitro metabolic stability using information-dependent acquisition on a hybrid triple quadrupole linear ion trap mass spectrometer",
abstract = "Rapid determination of in vitro metabolic stability and metabolite profiling of new chemical entities using microsomes or other liver preparations is one of the most important steps in drug discovery. In this paper, we report the use of liquid chromatography-hybrid triple quadrupole/linear ion trap mass spectrometry for the simultaneous analysis of metabolic stability, metabolite profiling, and the kinetics of metabolite formation of praziquantel and three structural analogs. Multiple reaction monitoring (MRM) scans were used to quantify the disappearance of parent compounds and the formation of metabolites. MRM-information dependent acquisition-enhanced product ion (MRM-IDA-EPI) scans were used for the identification of the metabolites formed. Metabolic stability of these anthelmintics were studied in human liver microsomes (HLM) using MRM as a survey scan, which resulted in the identification of a higher number of metabolites compared to neutral loss (NL), precursor ion (PI), and enhanced mass spectrometry (EMS) scans. MRM-IDA-EPI scans resulted in the generation of similar calibration curves to MRM-only quantitative analysis. Therefore, the quantitative capabilities of the method was not affected by the additional qualitative information obtained during the same run. The formation of major metabolites was also simultaneously monitored, which could be used to understand the kinetics and mechanism of metabolite formation. Finally, our data demonstrate that the three analogs had higher metabolic stability than the anthelmintic prototype (praziquantel).",
keywords = "Information-dependent acquisition, Metabolic stability, Metabolite profiling, Praziquantel, Structural analogs, Tandem mass spectrometry, Ultra-performance liquid chromatography",
author = "Jiangeng Huang and Bathena, {Sai Praneeth R.} and Yazen Alnouti",
year = "2010",
month = "1",
day = "1",
doi = "10.2133/dmpk.DMPK-10-RG-041",
language = "English (US)",
volume = "25",
pages = "487--499",
journal = "Drug Metabolism and Pharmacokinetics",
issn = "1347-4367",
publisher = "Japanese Society for the Study of Xenobiotics",
number = "5",

}

TY - JOUR

T1 - Metabolite profiling of praziquantel and its analogs during the analysis of in vitro metabolic stability using information-dependent acquisition on a hybrid triple quadrupole linear ion trap mass spectrometer

AU - Huang, Jiangeng

AU - Bathena, Sai Praneeth R.

AU - Alnouti, Yazen

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Rapid determination of in vitro metabolic stability and metabolite profiling of new chemical entities using microsomes or other liver preparations is one of the most important steps in drug discovery. In this paper, we report the use of liquid chromatography-hybrid triple quadrupole/linear ion trap mass spectrometry for the simultaneous analysis of metabolic stability, metabolite profiling, and the kinetics of metabolite formation of praziquantel and three structural analogs. Multiple reaction monitoring (MRM) scans were used to quantify the disappearance of parent compounds and the formation of metabolites. MRM-information dependent acquisition-enhanced product ion (MRM-IDA-EPI) scans were used for the identification of the metabolites formed. Metabolic stability of these anthelmintics were studied in human liver microsomes (HLM) using MRM as a survey scan, which resulted in the identification of a higher number of metabolites compared to neutral loss (NL), precursor ion (PI), and enhanced mass spectrometry (EMS) scans. MRM-IDA-EPI scans resulted in the generation of similar calibration curves to MRM-only quantitative analysis. Therefore, the quantitative capabilities of the method was not affected by the additional qualitative information obtained during the same run. The formation of major metabolites was also simultaneously monitored, which could be used to understand the kinetics and mechanism of metabolite formation. Finally, our data demonstrate that the three analogs had higher metabolic stability than the anthelmintic prototype (praziquantel).

AB - Rapid determination of in vitro metabolic stability and metabolite profiling of new chemical entities using microsomes or other liver preparations is one of the most important steps in drug discovery. In this paper, we report the use of liquid chromatography-hybrid triple quadrupole/linear ion trap mass spectrometry for the simultaneous analysis of metabolic stability, metabolite profiling, and the kinetics of metabolite formation of praziquantel and three structural analogs. Multiple reaction monitoring (MRM) scans were used to quantify the disappearance of parent compounds and the formation of metabolites. MRM-information dependent acquisition-enhanced product ion (MRM-IDA-EPI) scans were used for the identification of the metabolites formed. Metabolic stability of these anthelmintics were studied in human liver microsomes (HLM) using MRM as a survey scan, which resulted in the identification of a higher number of metabolites compared to neutral loss (NL), precursor ion (PI), and enhanced mass spectrometry (EMS) scans. MRM-IDA-EPI scans resulted in the generation of similar calibration curves to MRM-only quantitative analysis. Therefore, the quantitative capabilities of the method was not affected by the additional qualitative information obtained during the same run. The formation of major metabolites was also simultaneously monitored, which could be used to understand the kinetics and mechanism of metabolite formation. Finally, our data demonstrate that the three analogs had higher metabolic stability than the anthelmintic prototype (praziquantel).

KW - Information-dependent acquisition

KW - Metabolic stability

KW - Metabolite profiling

KW - Praziquantel

KW - Structural analogs

KW - Tandem mass spectrometry

KW - Ultra-performance liquid chromatography

UR - http://www.scopus.com/inward/record.url?scp=78449248269&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78449248269&partnerID=8YFLogxK

U2 - 10.2133/dmpk.DMPK-10-RG-041

DO - 10.2133/dmpk.DMPK-10-RG-041

M3 - Article

VL - 25

SP - 487

EP - 499

JO - Drug Metabolism and Pharmacokinetics

JF - Drug Metabolism and Pharmacokinetics

SN - 1347-4367

IS - 5

ER -