Reduction of systemic drug exposure after hepatic arterial infusion of doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration.
BACKGROUND
Hepatic arterial infusion of doxorubicin has produced tumor response in hepatic malignancies; however, the limited success of these treatments is related in part to dose-limiting systemic toxicities. The purpose of this study was to determine whether a novel venous isolation-chemofiltration system could limit systemic exposure to doxorubicin after hepatic arterial infusion.


METHODS
Doxorubicin (1 or 3 mg/kg) was infused in the hepatic arteries of domestic pigs after complete hepatic venous isolation was achieved with a dual-balloon vena cava catheter. The hepatic vein effluent was pumped through an extracorporeal carbon chemofiltration circuit. Doxorubicin levels were measured in prefilter (hepatic vein), postfilter, and systemic serum at intervals up to 1 hour after drug infusion.


RESULTS
Complete hepatic venous isolation with extracorporeal chemofiltration significantly reduced (> 90%) the postfilter and systemic levels of doxorubicin compared with prefilter levels (p < 0.01). At the time animals were killed 7 days after infusion of doxorubicin (3 mg/kg), tissue levels of doxorubicin in the liver showed a 16-fold increase compared with levels in the heart (p < 0.01).


CONCLUSIONS
For chemotherapeutic drugs like doxorubicin with a low first-pass extraction by the liver, the novel system described herein achieved significant reduction in systemic drug exposure. This system will allow dose intensification of doxorubicin administered by hepatic arterial infusion to treat hepatic malignancies.
Curley
S A
SA
Department of General Surgery, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Byrd
D R
DR
Newman
R A
RA
Ellis
H J
HJ
Chase
J
J
Carrasco
C H
CH
Cleary
K
K
Bodden
W
W
Hohn
D C
DC
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002118:Calcium / Q000097:blood; D002408:Catheters, Indwelling; D004317:Doxorubicin / Q000008:administration & dosage* / Q000097:blood* / Q000633:toxicity; D006440:Hemofiltration; D006454:Hemoglobins / Q000378:metabolism; D006499:Hepatic Artery; D006503:Hepatic Veins; D007261:Infusions, Intra-Arterial / Q000295:instrumentation; D007958:Leukocyte Count / Q000187:drug effects; D010976:Platelet Count / Q000187:drug effects; D012709:Serum Albumin / Q000378:metabolism; D013552:Swine
D001786:Blood Glucose; D001798:Blood Proteins; D006454:Hemoglobins; D012709:Serum Albumin; D004317:Doxorubicin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin; D002118:Calcium