In vitro partition of docetaxel and gemcitabine in human volunteer blood: the influence of concentration and gender

Dumez, Herlinde; Guetens, Gunther; Boeck, Gert De; Highley, Martin; Bruijn, E. A. de; Oosterom, A.T. van; Maes, R. A. A.

doi:10.1097/01.cad.0000175585.24317.ca

Cited by 13 publications

(6 citation statements)

References 12 publications

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“…In the range studied, there was a linear relationship between the quantity of CPT-11 in the RBCs and the whole-blood concentration (p = 0.0034). This phenomenon was also observed during incubation studies with docetaxel and gemcitabine [12]. This concentration-dependent rise in partition ratios of CPT-11 was not detected during our phase I studies with an oral formulation of CPT-11 [7,8], because the concentrations reached in vivo after oral dosing were much lower than the incubation concentrations in this study, which were based on the concentration range seen after i.v.…”

Section: Discussioncontrasting

confidence: 47%

In vitro partition of irinotecan (CPT-11) in human volunteer blood: the influence of concentration, gender and smoking

et al. 2005

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We have performed in vitro incubations of blood from male and female volunteers, smokers and non-smokers, with irinotecan at a gradient of different concentrations in order to investigate changes of partition between red blood cells (RBCs), total plasma and the free fraction. Since irinotecan (CPT-11) is not metabolized in vitro, there is no data available on its active metabolite SN-38. After extraction and sample pre-treatment, a validated high-performance liquid chromatography method followed by fluorescence detection was used to determine the concentration of the drug in the different blood constituents. The partition ratio [the concentration in the erythrocytes divided by the concentration in plasma (E/P)] was calculated. The partition ratio of CPT-11 varied from 0.7 to 2.8, reflecting its relatively high affinity for the erythrocyte, probably because of its only moderate plasma protein binding (65%). The partition ratios increased significantly with higher whole-blood concentrations, favoring uptake in the erythrocytes when plasma protein binding is saturated. No gender difference was detected, but we found relatively more CPT-11 in the erythrocytes of non-smokers compared to smokers. The incorporation of drugs into the RBC pool may be important for transportation to tumor tissue and efficacy. Smoking can have a significant influence on drug partition in the blood.

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Section: Discussioncontrasting

confidence: 47%

In vitro partition of irinotecan (CPT-11) in human volunteer blood: the influence of concentration, gender and smoking

et al. 2005

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“…It is reported that erythrocytes can play an important role in the transport of certain drugs [25,26]. This is not seen in sham or melphalan-treated tumors.…”

Section: Discussionmentioning

confidence: 99%

Early destruction of tumor vasculature in tumor necrosis factor-α-based isolated limb perfusion is responsible for tumor response

et al. 2006

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Addition of high-dose tumor necrosis factor-alpha to melphalan-based isolated limb perfusion enhances anti-tumor effects impressively. Unfortunately, the mechanism of action of tumor necrosis factor-alpha is still not fully understood. Here, we investigated the effects of tumor necrosis factor-alpha on the tumor microenvironment and on secondary immunological events during and shortly after isolated limb perfusion in soft-tissue sarcoma-bearing rats. Already during isolated limb perfusion, softening of the tumor was observed. Co-administration of tumor necrosis factor-alpha in the isolated limb perfusion with melphalan induced a six-fold enhanced drug accumulation of melphalan in the tumor compared with isolated limb perfusion with melphalan alone. In addition, directly after perfusion with tumor necrosis factor-alpha plus melphalan, over a time-frame of 30 min, vascular destruction, erythrocyte extravasation and hemorrhage was detected. Interstitial fluid pressure and pH in the tumor, however, were not altered by tumor necrosis factor-alpha and no clear immune effects, cellular infiltration or cytokine expression were observed. Taken together, these results indicate that tumor necrosis factor-alpha induces rapid damage to the tumor vascular endothelial lining resulting in augmented drug accumulation. As other important parameters were not changed (e.g. interstitial fluid pressure and pH), we speculate that the tumor vascular changes, and concurrent hemorrhage and drug accumulation are the key explanations for the observed synergistic anti-tumor response.

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“…However, data on the magnitude of potential distributional changes in dFdC and dFdU concentrations over time are sparse. In venous blood from eight healthy volunteers, the in vitro erythrocyte/plasma partition (EPP) ratio for dFdC was 1–5 in samples incubated with 0.500–100 μg/mL dFdC for 1 h at 37°C . Whether this corresponds to the in vivo EPP ratio in patients treated with 30‐min gemcitabine infusions is not known .…”

Section: Introductionmentioning

confidence: 99%

Preanalytical Stability of Gemcitabine and its Metabolite 2′, 2′-Difluoro-2′-Deoxyuridine in Whole Blood—Assessed by Liquid Chromatography Tandem Mass Spectrometry

Bjånes

Kamčeva

Eide

et al. 2015

Journal of Pharmaceutical Sciences

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Gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) and metabolite (2',2'-difluoro-2'-deoxyuridine, dFdU) quantification is warranted for individualized treatment strategies. Analyte stability is crucial for the validity of such quantification. We therefore studied the impact of the time interval from blood sampling to separation of plasma on gemcitabine stability. Blood from gemcitabine-treated patients was drawn into tetrahydrouridine (THU)-spiked heparin and ethylenediaminetetraacetic acid tubes and kept on ice until separation. Plasma was separated sequentially up to 24 h after sampling and dFdC and dFdU were quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS). The change in plasma concentrations over time was compared with the highest imprecision for concentrations above the lower limit of quantification of the LC-MS/MS method. Analyte concentrations decreased slightly over time, but for samples stored for 4 h on ice, the decline was smaller than the expected analytical imprecision. After 24 h, the maximum decline was 14.0%, which exceeded the expected analytical imprecision. dFdC and dFdU stabilities were acceptable for at least 4 h when THU-spiked whole blood samples were kept on ice. This is within the scope of routine sampling procedures. Further, variations in separation time intervals within this time frame are negligible when interpreting drug concentrations.

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In vitro partition of docetaxel and gemcitabine in human volunteer blood: the influence of concentration and gender

Cited by 13 publications

References 12 publications

In vitro partition of irinotecan (CPT-11) in human volunteer blood: the influence of concentration, gender and smoking

In vitro partition of irinotecan (CPT-11) in human volunteer blood: the influence of concentration, gender and smoking

Early destruction of tumor vasculature in tumor necrosis factor-α-based isolated limb perfusion is responsible for tumor response

Preanalytical Stability of Gemcitabine and its Metabolite 2′, 2′-Difluoro-2′-Deoxyuridine in Whole Blood—Assessed by Liquid Chromatography Tandem Mass Spectrometry

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