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 hepati c arterial infusion (HAI) and portal venous infusion (PVI) using a nov el system for hepatic venous isolation and charcoal hemoperfusion (HVI -CHP), The HVI-CHP system was used to determine directly the doxorubic in plasma concentration in the hepatic vein and the hepatic venous flo w rate, and simultaneously, to eliminate hepatic re-entry of the drug. Beagles received doxorubicin (1 mg/kg) through either the hepatic art ery (HAI group, n = 6) or the portal vein (PVI group, n = 6), In both groups, hepatic venous blood was completely isolated and directed to t he CHP filter, The filtered blood was returned through the left jugula r 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 tissu e uptake of doxorubicin was determined based on the blood flow rate an d 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 ei ther group, HVI-CHP produced a 66-87% reduction of the postfilter doxo rubicin level as compared with the prefilter level. The prefilter drug Level was significantly lower in HAI group than in PVI group (P < 0.0 1). Thus, the area under the time concentration curve for the prefilte r drug level in the HAI group (6.90 +/- 0.96 mu g min/ml) was signific antly lower than that in the PVI group (18.10 +/- 2.90 mu g 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 m ore effectively extracted by the liver when administered via the hepat ic artery than when administered via the portal vein. These results in dicate that HAI of doxorubicin is superior to PVI in terms of reductio n of systemic drug exposure and systemic toxicity.