Hepatic arterial infusion of verapamil and doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration: pharmacological evaluation of reduction in systemic drug exposure and assessment of hepatic toxicity.
Tumour resistance to chemotherapeutic drugs through expression of the multidrug resistance phenotype is a major impediment in the treatment of hepatic malignancies. We performed hepatic arterial infusion of verapamil (at a dose known to block P-glycoprotein activity) and doxorubicin combined with complete hepatic venous isolation and extracorporeal chemofiltration in non-tumour-bearing pigs with normal livers to evaluate the pharmacology and toxicology of this drug combination. The complete hepatic venous isolation-chemofiltration system significantly reduced system exposure to both verapamil and doxorubicin (P < 0.01). Hepatic arterial infusion of verapamil (2 mg/kg) alone did not result in hepatocellular toxicity. However, the combination of verapamil and doxorubicin (3 mg/kg or 5 mg/kg) produced significant elevations in liver enzymes (P < 0.01), and gross histological evidence of liver damage in 90% of the treated animals. The results of this study indicate that hepatic arterial infusion of verapamil and doxorubicin, in an attempt to improve treatment response in unresectable liver tumours expressing the multidrug resistance phenotype, may not be tolerated by patients with limited hepatic reserve.
Fuhrman
G M
GM
Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Cromeens
D M
DM
Newman
R A
RA
Cleary
K R
KR
Carrasco
C H
CH
Wright
K C
KC
Guercio
S
S
Guercio
A
A
Curley
S A
SA
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000633:toxicity; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D005112:Extracorporeal Circulation; D005374:Filtration; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial / Q000379:methods*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013552:Swine; D014700:Verapamil / Q000008:administration & dosage / Q000633:toxicity*
D004317:Doxorubicin; D014700:Verapamil