Skip to main content
SpringerLink
Log in

Pharmacokinetics and metabolism of the staurosporine analogue CGP 41 251 in mice

  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Abstract

Studies with CGP 41 251 (I), an N-benzoylstaurosporine derivative and PKC-α inhibitor, revealed that oral administration of 400 μg/day of the compound to wild type mice on four successive days reversed multi drug resistance (Killion et al. Oncology Research 7: 453–459, 1995). In our study, the same regimen of administration was followed with the primary objective to establish the pharmacokinetics and metabolism of the compound and to substantiate at which plasma concentrations of CGP 41 251 multi drug resistance (MDR) reversal can be expected. Concentrations of CGP 41 251 and metabolites in plasma were determined by a validated high performance liquid chromatography (HPLC) method with fluorescence detection. Structural characterization of the metabolites was performed with HPLC and mass spectrometric detection. In our experiment extensive metabolism of CGP 41 251 was found. The presence of five hydroxylated metabolites of CGP 41 251 (I) was confirmed and two metabolites were structurally elucidated as CGP 50 750 (III) and CGP 52 421 (V). Maximal concentrations of 73 ng/ml, 1.9 ng/ml and 126 ng/ml for CGP 41 251 (I), III and V were found, respectively. The mass spectra of the other three metabolites indicate that these are oxidized nitrogens or hydroxylated compounds. As yet, the oxidation or hydroxylation sites have not been established. This study has revealed new information about CGP 41 251 pharmacokinetics and metabolism. Target levels between 10–100 ng/ml may be important to achieve in further clinical trials with CGP 41 251 as MDR modulator.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sato W, Yusa K, Naito M, Tsuruo T: Staurosporine, a potent inhibitor of C-kinase, enhances drug accumulation in multidrug-resistant cells. Biochem Biophys Res Commun 173: 1252–1257, 1990

    Google Scholar 

  2. Andrejauskas-Buchdunger E, Regenass U: Differential inhibition of the epidermal growth factor-, platelet-derived growth factor-, and protein kinase C-mediated signal transduction pathways by the staurosporine derivative CGP 41 251. Cancer Res 52: 5353–5358, 1992

    Google Scholar 

  3. Fabbro D, Müller M, Meyer T, Regenass U: The PKC inhibitor CGP 41 251 reverses Pgp-mediated multidrug resistance and synergizes with adriamycin. Anti Cancer Drugs 5(suppl 1): 28, 1994

    Google Scholar 

  4. Inou M, Kishimoto A, Takai Y, Nishuzuka Y: Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues II. J Biol Chem 252: 7610–7616, 1977

    Google Scholar 

  5. Takai Y, Kishimoto A, Inoue M, Nishuzuka Y: Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues I. Purification and characterization of an active enzyme from bovine cerebellum. J Biol Chem 252: 7603–7609, 1977

    Google Scholar 

  6. Stryer L, Freeman WH: Biochemistry. Fourth edition. New York, 1995, pp 343–356

  7. Lu Z, Hornia A, Jiang YW, Zang Q, Foster DA: Tumor promoting by depleting cells of protein kinase C-delta. Mol Cell Biol 17: 3418–3428, 1997

    Google Scholar 

  8. Walker SD, Murray NR, Burns DJ, Fields AP: Protein kinase C chimeras: catalytic domain of alpha beta II protein kinase C contain determinants for isotype specific function. Proc Nat Acad Sci USA 92: 9156–9160, 1995

    Google Scholar 

  9. Gescher A: Modulators of signal transduction as cancer chemotherapeutic agents, novel mechanisms and toxicities. Toxicol Lett 82: 159–165, 1995

    Google Scholar 

  10. Bradshaw D, Hill CH, Nixon JS, Wilkinson SA: Therapeutic potential of protein kinase C inhibitors. Agents Action 38: 135–147, 1993

    Google Scholar 

  11. Basu A, Weixel K, Saijo N: Characterization of the protein kinase C signal transduction pathway in cisplatin-sensitive and-resistant human small cell lung carcinoma cells. Cell Growth Differ 7: 1507–1512, 1996

    Google Scholar 

  12. Cloud-Heflin BA, McMasters RA, Osborn MT, Chambers TC: Expression, subcellular distribution and response to phorbol esters of protein kinase C (PKC) isoenzymes in drug-sensitive and multidrug-resistant KB cells evidence for altered regulation of PKC-alpha. Eur J Biochem 239: 796–804, 1996

    Google Scholar 

  13. Bergman PJ, Gravitt KR, O'brian CA: An N-myristoylated protein kinase C-alpha pseudosubstrate peptide that functions as amultidrug resistance reversal agent in human breast cancer cells is not a P-glycoprotein substrate. Cancer Chem Phar 40: 453–456, 1997

    Google Scholar 

  14. Zini N, Neri LM, Ognibene A, Scotlandi K, Baldini M, Maraldi NM: Increase of nuclear phosphatidylinositol 4,5-biphosphate and phospholipase C beta 1 is not associated to variations of protein kinase C in multidrug-resistant Saos-2 cells. Microsc Res Tech 36: 172–178, 1997

    Google Scholar 

  15. Drew L, Groome N, Warr JR, Rumsby MG: Reduced daunomycin accumulation in drug-sensitive and multidrug-resistant human carcinoma KB cells following phorbol ester treatment: a potential role for PKC in reducing drug influx. Oncol Res 8: 249–257, 1996

    Google Scholar 

  16. Galaforo SS, Berns CM, Erdos G, Corry PM, Lee YJ: Hypoglycemia-induced AP-1 transcription factor and basic fibroblast growth factor gene expression in multidrug resistant human breast carcinoma MCF-7/ADR cells. Mol Chem Biol 155: 163–171, 1996

    Google Scholar 

  17. Fine RL, Chambers TC, Sachs CW: P-glycoprotein, multidrug resistance and protein kinase C. Stem Cells 14: 47–55, 1996

    Google Scholar 

  18. Basu A, Evans RW: Comparison of effects of growth factors and protein kinase C activators on cellular sensitivity to cisdiamminedichloroplatinum( II). Int J Cancer 58: 587–591, 1995

    Google Scholar 

  19. Grunicke I, Hofmann J, Utz I, Uberall F: Role of protein kinases in antitumor drug resistance. Oncol Hematol 69: 1–6, 1994

    Google Scholar 

  20. Basu A, Weixel K, Saijo N: Characterization of the protein kinase C signal transduction pathway in cisplatin-sensitive and-resistance human small cell lung carcinoma cells. Cell Growth and Diff 7: 1507–1512, 1996

    Google Scholar 

  21. Hunakova L, Sulikova M, Duraj J, Sedlak J, Chorvath B: Stimulation of Ara-C-induced apoptosis in the multidrug-resistant human promyelocytic leukemia cell lines with protein kinase C inhibitors. Neoplasma 43: 291–295, 1996

    Google Scholar 

  22. Killion JJ, Beltran P, O'Brian CA, Yoon S, Fan D, Wilson MR, Fidler IJ: The antitumor activity of doxorubicin against drug-resistance murine carcinoma is enhanced by oral administration of a synthetic staurosporine analogue, CGP 41 251. Oncol Research 7: 453–459, 1995

    Google Scholar 

  23. van Gijn R, van Tellingen O, de Clippeleir JJM, Hillebrand MJX, Boven E, Vermorken JB, ten Bokkel Huinink WW, Schwertz S, Graf P, Beijnen JH: Analytical procedure for the determination of the new antitumour drug Nbenzoylstaurosporine and three potential metabolites in human plasma by reversed-phase high-performance liquid chromatography. J Chromatogr B 667: 267–276, 1995

    Google Scholar 

  24. van Gijn R, Havik E, Boven E, Vermorken JB, ten Bokkel Huinink WW, van Tellingen O, Beijnen JH: High-performance liquid chromatographic analysis of the new antitumour drug N-benzoylstaurosporine (CGP 41 251) and four potential metabolites in micro-volumes of plasma. J Pharm Biomed Anal 14: 165–174, 1995

    Google Scholar 

  25. Gibaldi M, Perrier D: Pharmacokinetics, 2nd Edition, Marcel Dekker Inc, New York-Basel, 1982

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    R. van Gijn, E. Haverkate & J.H. Beijnen

  2. Department of Clinical Chemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    O. van Tellingen

  3. Department of Pharmaceutical Analysis and Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands

    J.J. Kettenes-van den Bosch & A. Bult

Authors
  1. R. van Gijn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. O. van Tellingen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Haverkate
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J.J. Kettenes-van den Bosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Bult
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J.H. Beijnen
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Gijn, R., van Tellingen, O., Haverkate, E. et al. Pharmacokinetics and metabolism of the staurosporine analogue CGP 41 251 in mice. Invest New Drugs 17, 29–41 (1999). https://doi.org/10.1023/A:1006260217400

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006260217400

Search

Navigation