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Use of hepatocytes isolated from a liver-humanized mouse for studies on the metabolism of drugs: application to the metabolism of fentanyl and acetylfentanyl

Kanamori, Tatsuyuki ; Togawa-Iwata, Yuko ; Segawa, Hiroki ; Yamamuro, Tadashi ; Kuwayama, Kenji ; Tsujikawa, Kenji ; Inoue, Hiroyuki

Forensic toxicology, 2018-07, Vol.36 (2), p.467-475 [Periódico revisado por pares]

Tokyo: Springer Japan

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  • Título:
    Use of hepatocytes isolated from a liver-humanized mouse for studies on the metabolism of drugs: application to the metabolism of fentanyl and acetylfentanyl
  • Autor: Kanamori, Tatsuyuki ; Togawa-Iwata, Yuko ; Segawa, Hiroki ; Yamamuro, Tadashi ; Kuwayama, Kenji ; Tsujikawa, Kenji ; Inoue, Hiroyuki
  • Assuntos: Forensic Medicine ; Forensic Science ; Medical Law ; Medicinal Chemistry ; Medicine ; Medicine & Public Health ; Original ; Original Article ; Pharmacology/Toxicology
  • É parte de: Forensic toxicology, 2018-07, Vol.36 (2), p.467-475
  • Descrição: Purpose The usefulness of hepatocytes isolated from a liver-humanized mouse (PXB-cells) as a model in vitro system for the prediction of the in vivo metabolism of new drugs of abuse was evaluated. Methods For the drug metabolism study, fentanyl, a powerful synthetic opioid, and acetylfentanyl, an N -acetyl analog of fentanyl, were selected as model drugs. PXB-cells were cultured with the drug for 24–48 h and then the media were collected and analyzed by liquid chromatography/mass spectrometry after deproteinization with acetonitrile. Results The main metabolite formed from fentanyl by PXB-cells was the desphenethylated metabolite (nor-fentanyl), and the other major metabolites formed were 4′-hydroxy-fentanyl, β-hydroxy-fentanyl and (ω-1)-hydroxy-fentanyl. ω-Hydroxy-fentanyl and 4′-hydroxy-3′-methoxy-fentanyl were the minor metabolites. Similar results were obtained for acetylfentanyl. The metabolite profile of fentanyl in PXB-cells was consistent with the in vivo metabolite profile of fentanyl reported previously. Most of the 4′-hydroxy- and 4′-hydroxy-3′-methoxy-metabolites of fentanyl and acetylfentanyl were conjugated in PXB-cells, indicating that PXB-cells had high conjugation enzyme activities. From experiments using human liver microsomes and anti-CYP antibodies, it was revealed that CYP3A4 was involved in the production of nor-fentanyl, β-hydroxy-fentanyl and (ω-1)-hydroxy-fentanyl, while CYP2D6 was partially involved in the production of 4′-hydroxy-fentanyl. Conclusions Our results indicated that PXB-cells have high activities of phase I and phase II drug-metabolizing-enzymes, can be stably supplied, and are easy to use; thus, PXB-cells are highly useful for the prediction of the in vivo metabolism of drugs of abuse.
  • Editor: Tokyo: Springer Japan
  • Idioma: Inglês
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