ORIGINAL ARTICLE Marc G. Sturgill á Dean E. Brenner á David A. August Augmentation of hepatic doxorubicin extraction with extracorporeal ®ltration avoids the dose-dependent, nonlinear increase in AUC observed with systemic administration Received: 6 February 1997 / Accepted: 9 May 1997 Abstract Purpose: Regional therapy of primary or metastatic liver cancer with low hepatic extraction ratio drugs such as doxorubicin is constrained by develop- ment of systemic toxicity. To examine the eect of augmentation of hepatic drug extraction, a swine model of hepatic artery infusion (HAI) with minimally invasive hepatic venous isolation and hepatic venous drug ex- traction (HVDE) was developed to study the compara- tive pharmacokinetic pro®les of regional and systemi- cally administered doxorubicin. Methods: Doxorubicin 0.5±9 mg/kg was administered to 31 pigs over 90 min either by HAI with simultaneous HVDE or by standard systemic vein infusion. Systemic artery and hepatic vein plasma samples were collected periodically (0 to 240 min) for determination of doxorubicin concentra- tions by high-performance liquid chromatography. Pharmacokinetic pro®les were modeled with PCNON- LIN 4.2. Results: Concentration-time data were best described in all pigs by a two-compartment open model of elimination. Independent of the route of administra- tion, AUC and C max values increased with dose. Mean systemic AUC and C max values were consistently lower with regional administration, with statistically signi®- cant decreases at the 0.5 and 3 mg/kg doses, whereas there was no relationship between hepatic vein param- eters and route of administration. There was a linear relationship between mean systemic AUC values and dose in pigs receiving doxorubicin via HAI with HVDE, whereas mean systemic AUC values increased expo- nentially at doses of 5 mg/kg or above with systemic vein administration. Conclusions: Administration of doxorubicin by HAI with simultaneous HVDE signi®- antly decreases systemic exposure in comparison with standard systemic vein drug infusion, and may protect against nonlinear increases in exposure at higher doses. Key words Doxorubicin á Pharmacokinetics á Hepatic artery infusion á Hepatic venous drug extraction á Area under the plasma concentration versus time curve á Maximum plasma concentration Introduction Doxorubicin (Fig. 1) is an anthracycline antibiotic with potent tumoricidal activity against a broad spectrum of hematologic and solid tumor types, including lympho- cytic and nonlymphocytic leukemias, Hodgkin's and non-Hodgkin's lymphomas, sarcomas, germ cell tumors, mesotheliomas, and carcinomas [34]. The tumoricidal activity of doxorubicin is attributed to several distinct DNA-disruptive processes [6, 9, 35, 40]. These processes, many of which are carried out by doxorubicin metabo- lites generated in the liver, include noncovalent interca- lation between 5¢-GC nucleotide base pairs in the DNA helix, classic DNA alkylation reactions, generation of oxygen free radical intermediates, and disruption of DNA repair via inhibition of topoisomerase I and II Cancer Chemother Pharmacol (1998) 41: 193±200 Ó Springer-Verlag 1998 M.G. Sturgill College of Pharmacy, Rutgers, The State University of New Jersey, New Jersey, USA M.G. Sturgill Division of Pediatric Pharmacology and Toxicology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, One Robert Wood Johnson Place CN-19, New Brunswick, New Jersey 08903, USA D.E. Brenner The Division of Hematology/Oncology, University of Michigan Medical School, Michigan, USA D.E. Brenner The Simpson Memorial Research Institute, 102 Observatory Street, Ann Arbor, Michigan 48109, USA D.A. August The Division of Surgical Oncology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA D.A. August (&) The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08901, USA Tel. (908) 235-7701; Fax (908) 235-7493