Verapamil-reversing concentrations induce blood flow changes that could counteract in vivo the MDR-1-modulating effects
✍ Scribed by Luis H. Ramirez; Jean-Nicolas Munck; Zhongxin Zhao; Caroline Bognel; Marcel Ricard; Patrice Ardouin; Philippe Rougier; Alain Gouyette
- Publisher
- John Wiley and Sons
- Year
- 1994
- Tongue
- English
- Weight
- 659 KB
- Volume
- 74
- Category
- Article
- ISSN
- 0008-543X
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✦ Synopsis
Background. Intraarterial hepatic (IAH) administration of verapamil should achieve mdr-1-reversing concentrations with reduced cardiac toxicity. The authors have explored the tolerance of its IAH administration and its effects on doxorubicin pharmacodynamics.
Methods. Verapamil was given to rabbits by intravenous or IAH administration, and its effects on heart rates were compared. Doxorubicin then was given intravenously either with IAH verapamil or with an IAH control perfusion, and tumor and liver drug concentrations were determined. Hepatic blood flow changes were studied by the administration of ggmTc-albumin macroaggregates (ag"Tc-MAA) under verapamil IAH perfusions.
Results. Compared with the intravenous route, IAH administration of verapamil was not toxic, and cardiac effects were reduced significantly. Its effect on doxorubicin distribution was detrimental, because the tumor-liver doxorubicin concentration ratios were lower in the verapamil group (0.23 vs. 3.37; P < 0.05). Tumor doxorubicin concentrations were lower when verapamil was coinfused (43 vs. 573 ng/100 mg tissue; P < 0.05). In normal liver tissue, increased amounts of doxorubicin and metabolites were observed. The verapamil IAH perfusions with ""Tc-MAA confirmed a differential action on tumor and normal vessels; the distribution of radionuclide was diverted away from the tumor bed significantly when verapamil was administered (tumor-to-liver ratio of 25.3