title: Verapamil-reversing concentrations induce blood flow changes that could counteract in vivo the MDR-1-modulating effects.
abstract: 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 pharmacodymamics.
  
  
  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 99mTc-albumin macroaggregates (99mTc-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 99mTc-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 control rabbits vs. 5.99 rabbits who received verapamil; P < 0.05).
  
  
  CONCLUSIONS
  Reversing the concentrations of verapamil provoked changes in the distribution of the liver blood flow. The hemodynamic effects of verapamil regional perfusions could counteract in vivo its potential mdr-1-reversing properties.
authors.affiliation: Département de Médecine, Institut Gustave-Roussy, Villejuif, France.
authors.forename: L H
authors.initials: LH
authors.lastname: Ramirez
authors.forename: J N
authors.initials: JN
authors.lastname: Munck
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.forename: C
authors.initials: C
authors.lastname: Bognel
authors.forename: M
authors.initials: M
authors.lastname: Ricard
authors.forename: P
authors.initials: P
authors.lastname: Ardouin
authors.forename: P
authors.initials: P
authors.lastname: Rougier
authors.forename: A
authors.initials: A
authors.lastname: Gouyette
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000378:metabolism*; D004361:Drug Tolerance; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008102:Liver Circulation / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*; D009368:Neoplasm Transplantation; D011817:Rabbits; D014700:Verapamil / Q000008:administration & dosage*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D004317:Doxorubicin; D014700:Verapamil