Different Enzyme Kinetics of Midazolam in Recombinant CYP3A4 Microsomes from Human and Insect Sources

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  • CHRISTENSEN Hege
    Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo
  • MATHIESEN Liv
    The Norwegian Medicines Agency
  • POSTVOLL Lillian W.
    Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo
  • WINTHER Bjørn
    Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo
  • MOLDEN Espen
    Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo

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  In vitro drug metabolism techniques with human CYP c-DNA expressed systems are frequently used to predict human drug metabolism in vivo. The aim of this study was to compare midazolam enzyme kinetics in recombinant expressed CYP3A4 microsomes from human and insect cells. The amounts of 1′- hydroxymidazolam and 4-hydroxymidazolam formed in CYP3A4 microsomes from transfected human liver epithelial cells (T5-3A4 microsomes) and baculovirus-infected insect cells (with and without coexpressed cytochrome b5) were analysed by LC-MS. Enzyme kinetic parameters were estimated by nonlinear regression. Mean Km for the formation of 1′-hydroxymidazolam was 3- and 4-fold higher in T5-3A4 microsomes than in insect microsomes (p<0.05), with and without coexpressed cytochrome b5, respectively. Only minor differences in Vmax were observed and the higher Km in T5-3A4 microsomes was reflected by significantly lower Clint compared to insect microsomes (p<0.001). For formation of 1′-hydroxymidazolam, human microsomes displayed Michaelis-Menten kinetics, while insect microsomes showed substrate inhibition kinetics. The different enzyme kinetics of midazolam observed in recombinant CYP3A4 microsomes from human and insect sources, especially the substantially higher Km obtained in human microsomes compared to insect microsomes, should be further evaluated since it may have implications for correlations to in vivo situation.<br>

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