Augmentation of hepatic doxorubicin extraction with extracorporeal filtration avoids the dose-dependent, nonlinear increase in AUC observed with systemic administration

Cancer Chemotherapy and Pharmacology
M G SturgillD A August

Abstract

Regional therapy of primary or metastatic liver cancer with low hepatic extraction ratio drugs such as doxorubicin is constrained by development of systemic toxicity. To examine the effect of augmentation of hepatic drug extraction, a swine model of hepatic artery infusion (HAI) with minimally invasive hepatic venous isolation and hepatic venous drug extraction (HVDE) was developed to study the comparative pharmacokinetic profiles of regional and systemically administered doxorubicin. 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 concentrations by high-performance liquid chromatography. Pharmacokinetic profiles were modeled with PCNONLIN 4.2. Concentration-time data were best described in all pigs by a two-compartment open model of elimination. Independent of the route of administration, AUC and Cmax values increased with dose. Mean systemic AUC and Cmax values were consistently lower with regional administration, with statistically significant decreases at the 0.5 and 3 mg/kg doses, whereas there was no relations...Continue Reading

Citations

Jul 13, 2005·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·C C ShihW C Lin
Mar 24, 2009·Regulatory Toxicology and Pharmacology : RTP·Julie I PapayChristine M Hunt
May 30, 2009·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·H UpurA Talip

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