Skip to main content
SpringerLink
Log in

Pharmacokinetic Analysis of Drug Disposition After Intratumoral Injection in a Tissue-Isolated Tumor Perfusion System

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. The purpose of this study was to establish an experimental system for evaluation of the intratumoral behavior of drugs after intratumoral injection using perfused tissue-isolated tumor preparations of Walker 256 carcinoma (3.46–9.73g, n = 16).

Methods. We quantified the recovery of Phenol Red (model drug) in the tumor, leakage from the tumor surface and the venous outflow after intratumoral injection using perfused tissue-isolated tumors, and analyzed venous appearance curves based on a pharmacokinetic model in which the tumor tissue was assumed to be divided into two compartments, i.e., well- and poorly-perfused regions.

Results. In small tumors (Type 1, 5.42 ± 0.39 g), the drug appeared immediately in the venous outflow, and the amount remaining in the tumor tissue at 2 hr after injection was small. In contrast, the venous appearance rate reached a significantly lower peak a few minutes after injection, and a large amount of injected drug remained in some large tumors (Type 2, 8.17 ± 0.51 g). Pharmacokinetic analysis revealed that there was a correlation between tumor weight and the rate constants of transfer from the poorly-perfused region to the well-perfused region, and between the rate constants of transfer from the well-perfused region to the venous outflow and dosing ratios into the well-perfused region.

Conclusions. An experimental system and analytical method were established for the evaluation of the intratumoral behavior of drugs after intratumoral injection using a tissue-isolated tumor perfusion system. This experimental system will be useful in analyzing the antitumor drug disposition after intratumoral injection.

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. Y. Takakura and M. Hashida. Critical Reviews in Oncology/Hematology 18:207–231 (1995).

    Google Scholar 

  2. M. Hashida, A. Kato, T. Kojima, S. Muranishi, H. Sezaki, N. Tanigawa, K. Satomura and Y. Hikasa. Gann 72:226–234 (1981).

    Google Scholar 

  3. W. A. Knepp, A. Jayakrishman, J. M. Quigg, H. S. Sitren, J. J. Bagnall and E. P. Goldberg. J. Pharm. Pharmacol. 45:887–891 (1993).

    Google Scholar 

  4. J. E. Landrito, K. Yoshiga, K. Sakurai and K. Takada. Anticancer Res. 14:113–118 (1994).

    Google Scholar 

  5. B. Zbar, I. D. Bernstein, G. L. Bartlett, Jr. M. G. Hanna and H. J. Rapp. J. Natl. Cancer Inst. 49:119–130 (1972).

    Google Scholar 

  6. C. A. McLaughlin, J. L. Cantrell, E. Ribi and E. P. Goldberg. Cancer Res. 38:1311–1316 (1978).

    Google Scholar 

  7. J. Kanellos, I. F. C. Mckenzie and G. A. Pietersz. Immunol. Cell Biol. 67:89–99 (1989).

    Google Scholar 

  8. L. T. M. Balemans, V. Mattijssen, P. A. Steerenberg, B. E. M. Van Driel, P. H. M. De Mulder, and W. Den Otter. Cancer Immunol. Immunother. 37:7–14 (1993).

    Google Scholar 

  9. T. Ebina, K. Murata and K. Tamura. Jpn. J. Cancer Res. 85:93–100 (1994).

    Google Scholar 

  10. I. Kitajima, T. Shinohara, T. Minor, L. Bibbs, J. Bilakovics and M. Nerenberg. J. Biol. Chem. 267:25881–25888 (1992).

    Google Scholar 

  11. M. Z. Ratajczak, J. A. Kant, S. M. Luger, N. Hijiya, J. Zhang, G. Zon and A. M. Gewirtz. Proc. Natl. Acad. Sci. USA 89:11823–11827 (1992).

    Google Scholar 

  12. G. E. Plautz, Z. Yang, B. Wu, X. Gao, L. Huang and G. J. Nabel. Proc. Natl. Acad. Sci. USA 90:4645–4649 (1993).

    Google Scholar 

  13. P. M. Gullino and F. H. Grantham. J. Natl. Cancer Inst. 27:679–693 (1961).

    Google Scholar 

  14. P.M. Gullino. In: BUSCH, H. (eds.) Methods in Cancer Research, Academic Press, New York, 1970, pp. 45–91.

    Google Scholar 

  15. E. G. Kristjansen Paul, S. Roberge, I. Lee, and R. K. Jain. Microvascular Research 48:389–402 (1994).

    Google Scholar 

  16. E. M. Sevick and R. K. Jain. Cancer Res. 49:3506–3512 (1989).

    Google Scholar 

  17. Y. Boucher, L. T. Baxter and R. K. Jain. Cancer Res. 50:4478–4484 (1990).

    Google Scholar 

  18. C. J. Eskey, A. P. Koretsky, M. M. Domach and R. K. Jain. Proc. Natl. Acad. Sci. USA 90:2646–2650 (1993).

    Google Scholar 

  19. K. Ohkouchi, H. Imoto, Y. Takakura, M. Hashida and H. Sezaki. Cancer Res. 50:1640–1644 (1990).

    Google Scholar 

  20. H. Imoto, Y. Sakamura, K. Ohkouchi, R. Atsumi, Y. Takakura, H. Sezaki and M. Hashida. Cancer Res. 52:4396–4401 (1992).

    Google Scholar 

  21. T. Kakutani, K. Yamaoka, M. Hashida and H. Sezaki. J. Pharmacokinet. Biopharm. 13:609–631 (1985).

    Google Scholar 

  22. K. Yamaoka, Y. Tanigawara, T. Nakagawa and T. Uno. J. Pharmacobio. Dyn. 4:879–885 (1981).

    Google Scholar 

  23. C. W. Song and S. H. Levitt. Cancer Res. 31:587–589 (1971).

    Google Scholar 

  24. R. K. Jain. Cancer Res. 48:2641–2658 (1988).

    Google Scholar 

  25. R. Gutmann, M. Leunig, J. Feyh, A. E. Goetz, K. Messmer, E. Kastenbauer and R. K. Jain. Cancer Res. 52:1993–1995 (1992).

    Google Scholar 

  26. R. K. Jain. Cancer Metastasis Rev. 6:559–593 (1987).

    Google Scholar 

  27. R. K. Jain. Cancer Res. 47:3039–3051 (1987).

    Google Scholar 

  28. T. P. Butler, F. H. Grantham and P. M. Gullino. Cancer Res. 35:3084–3088 (1975).

    Google Scholar 

  29. R. K. Jain. In: B. TEICHER (eds.), Drug resistance in oncology, New York: Marcel Dekker. 1993.

    Google Scholar 

  30. E. Nara, T. Hatono, M. Hashida and H. Sezaki. J. Pharm. Pharmacol. 15:272–274 (1991).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Drug Delivery Research, Faculty of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-01, Japan

    Akira Saikawa, Takehiko Nomura, Fumiyoshi Yamashita, Yoshinobu Takakura & Mitsuru Hashida

  2. Department of Pharmaceutics Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, 573-01, Japan

    Hitoshi Sezaki

Authors
  1. Akira Saikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takehiko Nomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fumiyoshi Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshinobu Takakura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hitoshi Sezaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mitsuru Hashida
    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

Saikawa, A., Nomura, T., Yamashita, F. et al. Pharmacokinetic Analysis of Drug Disposition After Intratumoral Injection in a Tissue-Isolated Tumor Perfusion System. Pharm Res 13, 1438–1444 (1996). https://doi.org/10.1023/A:1016054807555

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1016054807555

Search

Navigation