Regional pharmacokinetics of doxorubicin following hepatic arterial and portal venous administration: evaluation with hepatic venous isolation and charcoal hemoperfusion.
We evaluated the regional pharmacokinetics of doxorubicin after hepatic arterial infusion (HAI) and portal venous infusion (PVI) using a novel system for hepatic venous isolation and charcoal hemoperfusion (HVI-CHP). The HVI-CHP system was used to determine directly the doxorubicin plasma concentration in the hepatic vein and the hepatic venous flow rate, and simultaneously, to eliminate hepatic re-entry of the drug. Beagles received doxorubicin (1 mg/kg) through either the hepatic artery (HAI group, n = 6) or the portal vein (PVI group, n = 6). In both groups, hepatic venous blood was completely isolated and directed to the CHP filter. The filtered blood was returned through the left jugular vein. During HVI-CHP, the hepatic venous flow rate was monitored and plasma doxorubicin concentrations were serially measured in prefilter (= hepatic venous), postfilter, and systemic blood. The hepatic tissue uptake of doxorubicin was determined based on the blood flow rate and doxorubicin level in the hepatic vein. The hepatic extraction ratio of doxorubicin was defined as the percentage hepatic tissue uptake to the amount of drug administered. During drug infusion, similarly in either group, HVI-CHP produced a 66-87% reduction of the postfilter doxorubicin level as compared with the prefilter level. The prefilter drug level was significantly lower in HAI group than in PVI group (P < 0.01). Thus, the area under the time concentration curve for the prefilter drug level in the HAI group (6.90+/-0.96 microg min/ml) was significantly lower than that in the PVI group (18.10+/-2.90 microg min/ml, P < 0.01). Conversely, the hepatic extraction ratio in the HAI group (84.6+/-2.9%) was significantly higher than that in the PVI group (58.1+/-3.4%, P < 0.01). We conclude that in the beagle, doxorubicin is more effectively extracted by the liver when administered via the hepatic artery than when administered via the portal vein. These results indicate that HAI of doxorubicin is superior to PVI in terms of reduction of systemic drug exposure and systemic toxicity.
First Department of Surgery, Kobe University School of Medicine, Japan.
T
T
Iwasaki
Y
Y
Ku
N
N
Kusunoki
M
M
Tominaga
T
T
Fukumoto
S
S
Muramatsu
Y
Y
Kuroda
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D002606:Charcoal; D010478:Chemotherapy, Cancer, Regional Perfusion; D004285:Dogs; D004317:Doxorubicin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006464:Hemoperfusion / Q000379:methods*; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008102:Liver Circulation / Q000502:physiology; D008297:Male; D011169:Portal Vein
D000903:Antibiotics, Antineoplastic; D002606:Charcoal; D004317:Doxorubicin