Transarterial Chemoembolization with Doxorubicin; Drug Delivery and Pharmacokinetics
Morrison, Joseph D
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ABSTRACT Purpose Ethiodized oil (Lipiodol; Guerbet, Villepente France) is the standard drug delivery vehicle for conventional transarterial chemoembolization (c-TACE) and represents the benchmark for comparative studies evaluating novel TACE drug delivery modalities. This study aimed to define intra-tumoral and systemic pharmacokinetics, of doxorubicin (DOX) after Lipiodol-DOX c-TACE. Materials and methods VX2 tumors in the livers of 10 New Zealand white rabbits (mean weight, 2.7 ± 0.16kg) under-went DOX c-TACE. Systemic drug levels were measured using high performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) at 2, 5, 10, 15, 20, 30, 45, 60, 120 and 180 minutes post embolization. Intra-tumoral DOX retention was evaluated with HPLC-MS/MS after animal sacrifice at 180 minutes post-procedure, 1 day, 2 days, 4 days and 7 days (n=2/time point). Results were compared across time points using a paired samples T-test and one way analysis of variance (ANOVA) with a P value of <.05 being considered significant. Results DOx c-TACE was successfully performed in 10 cases via the left hepatic artery. Cmax attained for tumor tissue, liver parenchyma, and plasma were 6,741.5 ng/mL, 334.7 ng/mL, and 1,348.5 ng/mL respectively. Systemic levels of DOX were undetectable by 4 days post procedure. For the animals sacrificed at 180-minutes, 1 day, 2 days, 4 days and 7 days DOX concentrations were seen in the tumor and liver tissue at 5,989.8 ± 1,063 ng/mL and 173.5 ± 228 ng/ml, 1,715.6 ± 1,951.4 ng/ml and 194.2 ± 96.2 ng/ml, 956.5 ± 657.6 ng/ml and 45.7 ± 31.5 ng/ml, 1,547 ± 620.8 ng/ml and 112.9 ± 86.2 ng/ml, 216.9 ±80.6 ng/ml and 7.5 ±1.3 ng/ml respectively. The tumor tissue DOX concentration was significantly different (P=0.021) than the adjacent liver parenchyma at all time points by paired samples t-test analysis. Conclusion Results may suggest that DOX it is preferentially retained in tumor tissue for 7 days post c-TACE at pharmacologically relevant levels when compared to the adjacent normal liver parenchyma or systemic circulation.