An evaluation of hepatic extraction and clearance of doxorubicin

August, David A.; Verma, Nikhil; Vaertan, M. A.; Shah, Rehmat; Brenner, Dean E.

doi:10.1038/bjc.1995.278

Cited by 15 publications

(20 citation statements)

References 29 publications

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“…Mean systemic CL T values were consistently higher and t b values lower with HAI of doxorubicin, re¯ecting the supplemental clearance of drug by HVDE. This is not surprising, given the increase in hepatic doxorubicin extraction ratios (from 50±72% to 75±91%) previously reported with this method of doxorubicin administration [5,27]. Mean systemic CL T was signi®cantly increased with HAI/HVDE at the 5 mg/kg dose, although there were no signi®cant dierences in mean systemic t b values.…”

Section: Discussionsupporting

confidence: 61%

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

Sturgill

Brenner

August³

1997

Cancer Chemotherapy and Pharmacology

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Section: Discussionsupporting

confidence: 61%

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

Sturgill

Brenner

August³

1997

Cancer Chemotherapy and Pharmacology

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“…“Remote” samples of the liver (in areas far from the ablation and therefore not subject to hyperthermia) in our study were consistently about 5 μg/g. The absolute concentration values measured in the current study were considerably larger than in this prior modelling study, possibly in part due to the fact that normal liver tissue (vessel structure, stromal cells, interstitial pressure etc.,) is very different from tumor tissue and takes up doxorubicin very rapidly [ 34 ] compared to the tumor cells considered in the computer model [ 6 , 35 ]. The doxorubicin concentrations were consistently increased in the surrounding tissue volume, however with asymmetric distribution, most likely associated with variations in vascularity of liver tissue.…”

Section: Discussionmentioning

confidence: 99%

Increased Duration of Heating Boosts Local Drug Deposition during Radiofrequency Ablation in Combination with Thermally Sensitive Liposomes (ThermoDox) in a Porcine Model

Swenson

Haemmerich

Maul³

et al. 2015

PLoS ONE

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IntroductionRadiofrequency ablation (RFA) is used for the local treatment of liver cancer. RFA is effective for small (<3cm) tumors, but for tumors > 3 cm, there is a tendency to leave viable tumor cells in the margins or clefts of overlapping ablation zones. This increases the possibility of incomplete ablation or local recurrence. Lyso-Thermosensitive Liposomal Doxorubicin (LTLD), is a thermally sensitive liposomal doxorubicin formulation for intravenous administration, that rapidly releases its drug content when exposed to temperatures >40°C. When used with RFA, LTLD releases its doxorubicin in the vasculature around the zone of ablation-induced tumor cell necrosis, killing micrometastases in the ablation margin. This may reduce recurrence and be more effective than thermal ablation alone.PurposeThe purpose of this study was to optimize the RFA procedure used in combination with LTLD to maximize the local deposition of doxorubicin in a swine liver model. Pigs were anaesthetized and the liver was surgically exposed. Each pig received a single, 50 mg/m2 dose of the clinical LTLD formulation (ThermoDox®). Subsequently, ablations were performed with either 1, 3 or 6 sequential, overlapping needle insertions in the left medial lobe with total ablation time of 15, 45 or 90 minutes respectively. Two different RFA generators and probes were evaluated. After the final ablation, the ablation zone (plus 3 cm margin) was dissected out and examined for doxorubicin concentration by LC/MS and fluorescence.ConclusionThe mean Cmax of plasma total doxorubicin was 26.5 μg/ml at the end of the infusion. Overall, increased heat time from 15 to 45 to 90 minutes shows an increase in both the amount of doxorubicin deposited (up to ~100 μg/g) and the width of the ablation target margin to which doxorubicin is delivered as determined by tissue homogenization and LC/MS detection of doxorubicin and by fluorescent imaging of tissues.

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“…For the purpose of pharmacokinetic analysis, the data were treated as an intravenous bolus administration. In order to perform the curve fitting and calculation of the area under the time-concentration curve (AUC), the time concentration files were uploaded into Kaleidagraph (Synergy Software, Reading, PA) (9). In Kaleidagraph, the time-concentration curves were graphicallly displayed and the elimination portion of the time-concentration curves fit to a two compartment, exponential elimination equation: y =Ae -␣t + Be -␤t where A represents the y intercept of the first phase or redistributive phase, B represents the y intercept of the first order terminal phase, ␣ represents the slope of the first phase and ␤ represents the slope of the terminal phase (10).…”

Section: Methodsmentioning

confidence: 99%

“…In Kaleidagraph, the time-concentration curves were graphicallly displayed and the elimination portion of the time-concentration curves fit to a two compartment, exponential elimination equation: y =Ae -␣t + Be -␤t where A represents the y intercept of the first phase or redistributive phase, B represents the y intercept of the first order terminal phase, ␣ represents the slope of the first phase and ␤ represents the slope of the terminal phase (10). ␤ is considered equivalent to the elimination rate constant, k. The curves were intergrated using Kaleidagraph employing a modified trapezoidal rule for a user defined number of points between times 0 and the final measured concentration of thrombostatin within the linear portion of the curve (9). The segment of the AUC from the final measured concentration to infinity was estimated by the following equation: C*/k where C*= the final measured concentration and k = the elimination rate constant.…”

Section: Methodsmentioning

confidence: 99%

Thrombostatin Inhibits Induced Canine Coronary Thrombosis

Hasan¹,

Rebello²,

Smith³

et al. 1999

Thromb Haemost

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SummaryThrombostatin (RPPGF), an angiotensin converting enzyme metabolite of bradykinin, is an inhibitor of α-thrombin’s ability to activate platelets. We examined the in vivo pharmacokinetics and pharmacodynamics of thrombostatin in rabbits and its ability to inhibit coronary thrombosis induced by electrolytic injury in dogs. Plasma half-life of thrombostatin had a t1/2α of 2.6 min and a t1/2β of 24 min in rabbits. Ligating the renal arteries did not prolong clearance (t1/2α = 2.4 min; t1/2β = 12 min). Thrombostatin produced a prolonged in vivo antiplatelet effect. At 30 min after a single intravenous administration in rabbits, thrombostatin’s plasma concentration was <8.7 μM (5 μg/ml). However, ex vivo 20 and 40 nM γ-thrombin-induced platelet aggregation of these rabbits’ platelets was inhibited 40% for 2.75 and 1 h, respectively. In vitro, flow cytometry studies revealed that thrombostatin specifically bound to human platelets and washed human platelets treated with thrombostatin were less responsive to γ-thrombin than control platelets. Using electrolytic injury to induce coronary artery thrombosis, dogs treated with thrombostatin, aspirin, or combined thrombostatin and aspirin occluded in 62 ± 25 (mean ± SD), 62 ± 36, or 89 ± 32 min versus untreated animals which occluded at 39 ± 27 min, (p <0.01, p <0.01 and p <0.001, respectively). These studies show that thrombostatin binds to platelets and can delay coronary occlusion in vivo. Abbreviations: RPPGF: thrombostatin; PAR1: protease activated receptor 1, the first cloned thrombin receptor; PRP: platelet-rich plasma; PPP: plateletpoor plasma; LCX: left circumflex coronary artery; APTT: activated partial thromboplastin time; PT: prothrombin time

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An evaluation of hepatic extraction and clearance of doxorubicin

Cited by 15 publications

References 29 publications

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

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

Increased Duration of Heating Boosts Local Drug Deposition during Radiofrequency Ablation in Combination with Thermally Sensitive Liposomes (ThermoDox) in a Porcine Model

Thrombostatin Inhibits Induced Canine Coronary Thrombosis

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