Cancer Chemotherapy and Pharmacology

, Volume 33, Issue 5, pp 425–434 | Cite as

Plasma pharmacokinetics, tissue disposition, excretion and metabolism of vinleucinol in mice as determined by high-performance liquid chromatography

  • Olaf van Tellingen
  • Anneloes L. C. Sonneveldt
  • Jos H. Beijnen
  • Willem J. Nooijen
  • Jantien J. Kettenes-van den Bosch
  • Cornelis Versluis
  • Auke Bult
Original Articles Vinca Alkaloids, Pharmacokinetics, HPLC, Plasma, Tissue, Metabolism


We investigated the pharmacokinetics of the experimental semisynthetic vinca alkaloid vinleucinol (VileE; O4-deacetyl-3-de(methoxycarbonyl)-3-[[[1-ethoxycarbonyl-2-methylbutyl]amino]carbonyl]-vincaleukoblastine). The study was performed in male FVB mice receiving 10.5 mg/kg VileE i.v. or p.o. Plasma, urine, faeces and tissue samples were analysed by a selective method based on ion-exchange normal-phase high-performance liquid chromatography (HPLC) with fluorescence detection and liquid-liquid extraction for sample clean-up. Apart from the parent drug, two other metabolic compounds were detected. One of these metabolites is vinleucinol acid (VileA; O4-deacetyl-3-de(methoxycarbonyl)-3-[[[1-carboxyl-2-methylbutyl]amino]carbonyl]-vincaleukoblastine), which possesses no cytotoxic activity. The structure proposed for the second metabolite (VileX) was based on tandem mass spectrometry (MS-MS) and infrared (IR) spectroscopy data. Metabolization of VileE to VileX must occur in the amino acid moiety of the molecule, with a (β- or γ-) lactone ring being formed after oxidation of the (β- or γ) carbon of the amino acid. VileX is a major metabolite, which is excreted in faeces and urine after i.v. administration and accounting for up to 23% of the administered dose. The activity of VileX against cultured L1210 cells is four times that of the parent drug VileE and comparable with that of vinblastine (VBL). At 48 h after administration of VileE, the concentration of VileX exceeds that of the parent drug in many tissues. These findings indicate that the metabolite VileX may be at least largely responsible for the activity observed against xenografts in mice after administration of the parent drug, VileE.


Alkaloid Lactone Vinblastine Parent Drug L1210 Cell 
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Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Olaf van Tellingen
    • 1
  • Anneloes L. C. Sonneveldt
    • 1
  • Jos H. Beijnen
    • 2
  • Willem J. Nooijen
    • 1
  • Jantien J. Kettenes-van den Bosch
    • 3
  • Cornelis Versluis
    • 4
  • Auke Bult
    • 3
  1. 1.Department of Clinical ChemistryNetherlands Cancer Institute, Antoni van LeeuwenhoekhuisAmsterdamThe Netherlands
  2. 2.Department of PharmacySlotervaart HospitalAmsterdamThe Netherlands
  3. 3.Department of Pharmaceutical Analysis, Faculty of PharmacyUtrecht UniversityUtrechtThe Netherlands
  4. 4.Faculty of ChemistryBijvoet Center for Biomolecular Research Mass Spectrometry Group, Utrecht UniversityUtrechtThe Netherlands

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