Metabolites of lorazepam: Relevance of past findings to present day use of LC-MS/MS in analytical toxicology: Relevance of past findings to present day use of LC-MS/MS in analytical toxicology

TY - JOUR

T1 - Metabolites of lorazepam: Relevance of past findings to present day use of LC-MS/MS in analytical toxicology

T2 - Relevance of past findings to present day use of LC-MS/MS in analytical toxicology

AU - Turfus, Sophie C.

AU - Braithwaite, Robin A.

AU - Cowan, David A.

AU - Parkin, Mark C.

AU - Smith, Norman W.

AU - Kicman, Andrew T.

PY - 2011/10

Y1 - 2011/10

N2 - The advent of liquid chromatography-tandem mass spectrometry (LC-MS/MS), with the sensitivity it confers, permits the analysis of both phase I and II drug metabolites that in the past would have been difficult to target using other techniques. These metabolites may have relevance to current analytical toxicology employing LC-MS/MS, and lorazepam was chosen as a model drug for investigation, as only the parent compound has been targeted for screening purposes. Following lorazepam administration (2 mg, p.o.) to 6 volunteers, metabolites were identified in urine by electrospray ionization LC-MS/MS, aided by the use of deuterated analogues generated by microsomal incubation for use as internal chromatographic and mass spectrometric markers. Metabolites present were lorazepam glucuronide, a quinazolinone, a quinazoline carboxylic acid, and two hydroxylorazepam isomers, one of which is novel, having the hydroxyl group located on the fused chlorobenzene ring. The quinazolinone, and particularly the quinazoline carboxylic acid metabolite, provided longer detection windows than lorazepam in urine extracts not subjected to enzymatic hydrolysis, a finding that is highly relevant to toxicology laboratories that omit hydrolysis in order to rapidly reduce the time spent on gas chromatography-mass spectrometry (GC-MS) analysis. With hydrolysis, the longest windows of detection were achieved by monitoring lorazepam, supporting the targeting of the aglycone with free drug for those incorporating hydrolysis in their analytical toxicology procedures. Copyright (C) 2011 John Wiley & Sons, Ltd.

AB - The advent of liquid chromatography-tandem mass spectrometry (LC-MS/MS), with the sensitivity it confers, permits the analysis of both phase I and II drug metabolites that in the past would have been difficult to target using other techniques. These metabolites may have relevance to current analytical toxicology employing LC-MS/MS, and lorazepam was chosen as a model drug for investigation, as only the parent compound has been targeted for screening purposes. Following lorazepam administration (2 mg, p.o.) to 6 volunteers, metabolites were identified in urine by electrospray ionization LC-MS/MS, aided by the use of deuterated analogues generated by microsomal incubation for use as internal chromatographic and mass spectrometric markers. Metabolites present were lorazepam glucuronide, a quinazolinone, a quinazoline carboxylic acid, and two hydroxylorazepam isomers, one of which is novel, having the hydroxyl group located on the fused chlorobenzene ring. The quinazolinone, and particularly the quinazoline carboxylic acid metabolite, provided longer detection windows than lorazepam in urine extracts not subjected to enzymatic hydrolysis, a finding that is highly relevant to toxicology laboratories that omit hydrolysis in order to rapidly reduce the time spent on gas chromatography-mass spectrometry (GC-MS) analysis. With hydrolysis, the longest windows of detection were achieved by monitoring lorazepam, supporting the targeting of the aglycone with free drug for those incorporating hydrolysis in their analytical toxicology procedures. Copyright (C) 2011 John Wiley & Sons, Ltd.

KW - Benzodiazepines

KW - lorazepam

KW - LC-MS/MS

KW - forensic

KW - drug metabolism

KW - analytical toxicology

KW - TANDEM MASS-SPECTROMETRY

KW - SOLID-PHASE EXTRACTION

KW - FACILITATED SEXUAL ASSAULT

KW - GAS-CHROMATOGRAPHY

KW - HUMAN URINE

KW - DIASTEREOISOMERIC GLUCURONIDES

KW - N-DEMETHYLATION

KW - BENZODIAZEPINES

KW - IDENTIFICATION

KW - DRUG

U2 - 10.1002/dta.305

DO - 10.1002/dta.305

M3 - Article

C2 - 21837620

SN - 1942-7603

VL - 3

SP - 695

EP - 704

JO - Drug Testing And Analysis

JF - Drug Testing And Analysis

IS - 10

ER -