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

Abstract

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.

Keywords

Alkaloid Lactone Vinblastine Parent Drug L1210 Cell 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bhushana Rao KSP, Collard MP, Trouet A (1985) Vinca-23-oyl amino acid derivatives as new anticancer agents (review). Anticancer Res 5: 379–386Google Scholar
  2. 2.
    Cersosimo RJ, Bromer R, Licciardello JTW, Ki Hong W (1983) Pharmacology, clinical efficacy and adverse effects of vindesine sulfate, a new vinca alkaloid. Pharmacotherapy 3: 259–274Google Scholar
  3. 3.
    Cutts JH, Beer CT, Noble RL (1960) Biological properties of vincaleukoblastine, an alkaloid inVinca rosea Linn, with reference to its antitumour action. Cancer Res 20: 1023–1031Google Scholar
  4. 4.
    Depierre A, Lemarie E, Dabouis G, Garnier G, Jacoulet P, Dalphin JC (1991) A phase II study of navelbine (vinorelbine) in the treatment of non-small-cell lung cancer. Am J Clin Oncol 14: 115–119Google Scholar
  5. 5.
    Dyke RW, Nelson RL (1977) Phase I anti-cancer agents vindesine (desacetyl vinblastine amide sulfate). Cancer Treat Rev 4: 135–142Google Scholar
  6. 6.
    Hendriks HR, Langdon S, Berger DP, Breistol K, Fiebig HH, Fodstad O, Schwartsmann G (1992) Comparative antitumour activity of vinblastine-isoleucinate and related vinca alkaloids in human tumour xenografts. Eur J Cancer 28A: 767–773Google Scholar
  7. 7.
    Johnson IS (1968) Historical background of vinca alkaloid research and areas of future interest. Cancer Chemother Rep 52: 455–461Google Scholar
  8. 8.
    Johnson IS, Wright HF, Svoboda GH (1959) Experimental basis for clinical evaluation of anti-tumour principles derived fromVinca rosea Linn. J Lab Clin Med 54: 830Google Scholar
  9. 9.
    Johnson IS, Armstrong JG, Gorman M, Burnett JP Jr (1963) The vinca alkaloids: a new class of oncolytic agents. Cancer Res 23: 1390–1427Google Scholar
  10. 10.
    Kreis W, Budman DR, Freeman J, Bergstrom RF, Nelson RL (1990) Clinical pharmacokinetics of intravenously injected tritiated vinzolidine. Cancer Chemother Pharmacol 26: 419–422Google Scholar
  11. 11.
    Neuss N, Fukada DS, Mallett GE, Brannon DR, Huckstep LL (1973) Vinca alkaloids. XXXII. Microbiological conversions of vindoline, a major alkaloid fromVinca rosea L. Helv Chim Acta 56: 2418–2426Google Scholar
  12. 12.
    Pierŕe A, Kraus-Berthier L, Atassi G, Cros S, Poupon MF, Lavielle G, Berlion M, Bizzari JP (1991) Pre-clinical antitumour activity of a new vinca alkaloid derivative, S 12363. Cancer Res 51: 2312–2318Google Scholar
  13. 13.
    Svoboda GH (1961) Alkaloids fromVinca rosea Linn. IX. Extraction and characterization of leurosidine and leurocristine. Lloydia 24: 173–178Google Scholar
  14. 14.
    Tafur S, Jones WE, Dorman DE, Logsdon EE, Svoboda GH (1975) Alkaloids ofVinca rosea L. (Catharanthus roseus G, Don) XXXVI: Isolation and characterisation of new dimeric alkaloids. J Pharm Sci 64: 1953–1957Google Scholar
  15. 15.
    Ten Bokkel Huinink WW, Belpomme D, Franklin H, Fumoleau R, Verweij J (1992) Phase II screening program of vintriptol in breast cancer, melanoma, colorectal cancer and lung cancer. Ann Oncol 3 [Suppl 1]: 126Google Scholar
  16. 16.
    Van Tellingen O, Beijnen JH, Nooijen WJ (1991) Analytical methods for the determination of vinca alkaloids in biological material. J Pharm Biomed Anal 9: 1077–1082Google Scholar
  17. 17.
    Van Tellingen O, Beijnen JH, Baurain R, Ten Bokkel Huinink WW, Van der Woude HR, Nooijen WJ (1992) Bioanalysis of vintriptol-acid, a metabolite of vintriptol, by high-performance liquid chromatography with fluorescence detection. J Chromatogr 574: 293–398Google Scholar
  18. 18.
    Van Tellingen O, Sips JH, Beijnen JH, Bult A, Nooijen WJ (1992) Pharmacology, bioanalysis and pharmacokinetics of the vinca alkaloids and semi-synthetic derivatives (review). Anticancer Res 5: 1699–1715Google Scholar
  19. 19.
    Van Tellingen O, Beijnen JH, Nooijen WJ, Bult A (1993) Tissue disposition, excretion and metabolism of vinblastine in mice as determined by high performance liquid chromatography. Cancer Chemother Pharmacol 32: 286–292Google Scholar

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

Personalised recommendations