Doxorubicin pharmacokinetics: Macromolecule binding, metabolism, and excretion in the context of a physiologic model

Gustafson, Daniel L.; Rastatter, Jeffrey C.; Colombo, Tina; Long, Michael E.

doi:10.1002/jps.10161

Cited by 87 publications

(80 citation statements)

References 40 publications

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“…The peak concentration of total EPI in plasma is 9.71 ± 1.07 mg/L at 1 min after injection and then decreased to nearly undetectable levels after 24 h. The free EPI rapidly disappears from the circulation due to its short half-life (t 1/2 ). In this study, the t 1/2 of free EPI is 6.95 ± 0.51 h, which is consistent with that of 7.3 ± 1.8 h of doxorubicin (Gustafson et al, 2002). Whereas the t 1/2 of EPI-CHSPNs is 2.8-fold longer than that of free EPI.…”

Section: In Vivo Toxicity Of Chspnssupporting

confidence: 88%

The preliminary evaluation on cholesterol-modified pullulan as a drug nanocarrier

Shen

Yang

2014

Drug Delivery

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To further develop cholesterol-modified pullulan self-aggregated nanoparticles (CHSPNs) as a drug nanocarrier, CHSP was synthesized and characterized. Its cholesterol degree determined by 1 H NMR was 5.2 cholesterol groups per hundred glucose units. CHSPNs were prepared in aqueous media and characterized by dynamic laser light-scattering (DLS), zeta potential and transmission electron microscopy (TEM). These nanoparticles were almost spherical in shape, and the zeta potentials of CHSPNs were near zero in aqueous media. CHSPNs can be stable at least 2 months with no significant size and zeta potential changes. Single dose toxicity test in mice was investigated for the safety evaluation of CHSPNs as a drug nanocarrier, and the result showed CHSPNs were well tolerated at the dose of 200 mg/kg in mice. Epirubicin (EPI)-loaded CHSPNs (EPI-CHSPNs) were prepared and the in vivo pharmacokinetics and biodistribution were studied. Compared with the EPI solution, EPI-CHSPNs have exhibited higher plasma drug concentration, longer half-life time (t 1/2 ) and the larger area under-the-curve (AUC). Moreover, the drug level of EPI-CHSPNs increased in liver and decreased in heart. The results indicated that CHSPNs were stable, safe and may be a promising drug delivery carrier.

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Section: In Vivo Toxicity Of Chspnssupporting

confidence: 88%

The preliminary evaluation on cholesterol-modified pullulan as a drug nanocarrier

Shen

Yang

2014

Drug Delivery

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“…According to the previous report (Mross et al, 1988;Jakobsen et al, 1991;1994), free EPI rapidly disappeared from the circulation due to its short half-life. In this study, the terminal elimination half-life of free EPI was 8.129 h (Table 5), which was consistent with that of 7.3 h of doxorubucin (Gustafson et al, 2002;Bibby et al, 2005). In contrast, PA/EPI showed a much longer circulation time and its elimination half-life time was 17.231 h, 2.12-times that of free EPI.…”

Section: In Vivo Pharmacokineticssupporting

confidence: 83%

Stability and in vivo evaluation of pullulan acetate as a drug nanocarrier

Tang

Chen

et al. 2010

Drug Delivery

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“…This was associated with increased apoptosis, decreased microvessel density, and local necrosis. The observed differential effects of aflibercept on patterns of doxorubicin accumulation and vascular changes in marrow versus s.c. tumor locations support the site-specific heterogeneity of leukemia vasculature and in vivo doxorubicin pharmacokinetics (47). Although p-glycoprotein expression by human HL60/VCR cells may theoretically have enhanced intracellular drug levels in this model (23), we noted similar results in a second (HEL) AML model lacking multidrug efflux protein expression.…”

Section: Discussionsupporting

confidence: 73%

Aflibercept Exerts Antivascular Effects and Enhances Levels of Anthracycline ChemotherapyIn vivoin Human Acute Myeloid Leukemia Models

Lal

Park

Demock

et al. 2010

Molecular Cancer Therapeutics

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We examined whether potent vascular endothelial growth factor (VEGF) blockade mediated by aflibercept, a decoy VEGF receptor (VEGFR) 1/2 moiety with stronger affinity for VEGF than bevacizumab, resulted in antileukemia effects and enhanced the efficacy of systemic chemotherapy. The efficacy of aflibercept alone and in combination with doxorubicin was evaluated in human VEGF-expressing acute myeloid leukemia (AML) cell lines and primary cells xenotransplanted into immunodeficient mice. Aflibercept reduced primary VEGF/VEGFR-positive AML colony formation growth in vitro and inhibited AML xenograft growth up to 93% in association with antiangiogenic and antiproliferative effects, hypoxia, and VEGF sequestration in multiple models. High VEGF-A expression by AML cells promoted in vivo xenograft growth and aflibercept sensitivity. Aflibercept therapy slowed disease progression in two systemic human AML xenograft models and reduced peripheral leukemia disease in a primary relapsed AML model in NOD/SCID/IL2Rγnull mice. Combination aflibercept and doxorubicin enhanced antitumor effects in local xenograft models. Sequential aflibercept followed by doxorubicin resulted in progressive anthracycline accumulation in marrow and extramedullary AML sites and resulted in 2-fold higher drug levels 24 hours after administration. In contrast, tissues (tumor, plasma, marrow) treated with chemotherapy only showed progressive drug clearance over time. Combination aflibercept and doxorubicin also resulted in vascular narrowing, decreased vessel number, and perivascular apoptosis. These data suggest that inefficient drug delivery by leukemia-associated vasculature may mediate chemoresistance and support further clinical evaluation of combination aflibercept and anthracycline therapy in refractory/relapsed AML patients. Mol Cancer Ther; 9(10);

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Doxorubicin pharmacokinetics: Macromolecule binding, metabolism, and excretion in the context of a physiologic model

Cited by 87 publications

References 40 publications

The preliminary evaluation on cholesterol-modified pullulan as a drug nanocarrier

The preliminary evaluation on cholesterol-modified pullulan as a drug nanocarrier

Stability and in vivo evaluation of pullulan acetate as a drug nanocarrier

Aflibercept Exerts Antivascular Effects and Enhances Levels of Anthracycline ChemotherapyIn vivoin Human Acute Myeloid Leukemia Models

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