Determination of midazolam and its metabolite as a probe for cytochrome P450 3A4 phenotype by liquid chromatography-mass spectrometry

Hideko Kanazawa, Akiko Okada, Eri Igarashi, Megumu Higaki, Takako Miyabe, Tadashi Sano, Ryouhei Nishimura

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

This study demonstrated the analysis of midazolam and its metabolites by liquid chromatography-mass spectrometry (LC-MS) with a sonic spray ionization (SSI) interface. The analytical column was a YMC-Pak Pro C18 (50mm x 2.0mm i.d.) using 10mM ammonium acetate (pH 4.8)-methanol (1:1) at a flow rate of 0.2mlmin-1. The drift voltage was 100V. The sampling aperture was heated at 110°C and the shield temperature was 230°C. The lower limits for the detection of midazolam and 1′-hydroxymidazolam were 26.3 and 112.76pg injected, respectively. The calibration curves for midazolam and 1′-hydroxymidazolam were linear in the range of 0.1-5μgml -1. Within-day relative standard deviations was less than 7%. The method was applied to the determination of midazolam in monkey plasma, and the analysis of midazolam and its metabolites in an in vitro study with recombinant cytochrome P450 (CYP) 3A4. This method is sufficiently sensitive and useful to elucidate the kinetics of midazolam metabolite formation. We also investigated the effect of propofol on the metabolism of midazolam using recombinant CYP3A4. Propofol competitively inhibited the metabolism of midazolam to 1′-hydroxymidazolam by CYP3A4.

Original languageEnglish
Pages (from-to)213-218
Number of pages6
JournalJournal of Chromatography A
Volume1031
Issue number1-2
DOIs
Publication statusPublished - 2004 Mar 26

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Cytochrome P-450 CYP3A
Midazolam
Liquid chromatography
Metabolites
Liquid Chromatography
Mass spectrometry
Mass Spectrometry
Phenotype
Propofol
Metabolism
Calibration
Ionization
Haplorhini
Methanol
Limit of Detection
Flow rate
Sampling
Plasmas
Kinetics
Temperature

Keywords

  • Cytochromes
  • Interfaces, LC-MS
  • Midazolam
  • Propofol
  • Sonic spray ionization

ASJC Scopus subject areas

  • Analytical Chemistry

Cite this

Determination of midazolam and its metabolite as a probe for cytochrome P450 3A4 phenotype by liquid chromatography-mass spectrometry. / Kanazawa, Hideko; Okada, Akiko; Igarashi, Eri; Higaki, Megumu; Miyabe, Takako; Sano, Tadashi; Nishimura, Ryouhei.

In: Journal of Chromatography A, Vol. 1031, No. 1-2, 26.03.2004, p. 213-218.

Research output: Contribution to journalArticle

Kanazawa, Hideko ; Okada, Akiko ; Igarashi, Eri ; Higaki, Megumu ; Miyabe, Takako ; Sano, Tadashi ; Nishimura, Ryouhei. / Determination of midazolam and its metabolite as a probe for cytochrome P450 3A4 phenotype by liquid chromatography-mass spectrometry. In: Journal of Chromatography A. 2004 ; Vol. 1031, No. 1-2. pp. 213-218.
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