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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Reduced Liver Uptake of Arterially Infused Melphalan during Retrograde Rat Liver Perfusion with Unaffected Liver Tumor Uptake

Joost Rothbarth, Rolf W. Sparidans, Jos H. Beijnen, Leo J. Schultze Kool, Hein Putter, Cornelis J. H. van de Velde and Gerard J. Mulder
Journal of Pharmacology and Experimental Therapeutics November 2002, 303 (2) 736-740; DOI: https://doi.org/10.1124/jpet.102.037895
Joost Rothbarth
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Rolf W. Sparidans
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Jos H. Beijnen
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Leo J. Schultze Kool
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Hein Putter
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Cornelis J. H. van de Velde
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Gerard J. Mulder
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Abstract

Isolated hepatic perfusion (IHP) with melphalan is used for patients with nonresectable metastases confined to the liver. To improve the efficacy of IHP and to reduce the toxicity to the liver, reversion (retrograde perfusion) of the bloodstream through the liver in a rat model was studied. For liver tumor induction male WAG/Rij rats were inoculated with CC531 cells, a colorectal tumor cell line. After 11 to 12 days the tumor-bearing rat livers were perfused by single-pass perfusion through either the portal (orthograde) or caval vein (retrograde) for different time periods. During perfusion melphalan (160 μM) was infused in the hepatic artery. Melphalan concentrations were measured by high-performance liquid chromatography. A rapid extraction of melphalan by the liver occurred in the first 5 min, reaching steady state after 10 to 20 min for both perfusion directions. The melphalan concentration of the outflow perfusate was significantly higher in the retrograde perfusion compared with the orthograde perfusion. The melphalan content of the tumor tissue was unaffected by perfusion direction at any time point. To the contrary, the melphalan uptake in liver tissue was strongly influenced: the melphalan content after 40-min retrograde perfusion was 12% of that after orthograde perfusion. The average tumor/liver concentration ratio was 6 for orthograde perfusion and 30 for retrograde perfusion. In conclusion, retrograde IHP with continuous melphalan infusion in the hepatic artery provides a high tumor uptake of melphalan with potentially reduced liver toxicity compared with orthograde IHP.

Footnotes

  • This study was supported by Grant 2000-2198 from the Dutch Cancer Society (to K.W.F.).

  • DOI: 10.1124/jpet.102.037895

  • Abbreviations:
    IHP
    isolated hepatic perfusion
    HPLC
    high-performance liquid chromatography
    dp
    particle density
    • Received April 23, 2002.
    • Accepted July 22, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 303 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 2
1 Nov 2002
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Reduced Liver Uptake of Arterially Infused Melphalan during Retrograde Rat Liver Perfusion with Unaffected Liver Tumor Uptake

Joost Rothbarth, Rolf W. Sparidans, Jos H. Beijnen, Leo J. Schultze Kool, Hein Putter, Cornelis J. H. van de Velde and Gerard J. Mulder
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 736-740; DOI: https://doi.org/10.1124/jpet.102.037895

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Reduced Liver Uptake of Arterially Infused Melphalan during Retrograde Rat Liver Perfusion with Unaffected Liver Tumor Uptake

Joost Rothbarth, Rolf W. Sparidans, Jos H. Beijnen, Leo J. Schultze Kool, Hein Putter, Cornelis J. H. van de Velde and Gerard J. Mulder
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 736-740; DOI: https://doi.org/10.1124/jpet.102.037895
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