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Skeletal Muscle an Active Compartment in the Sequestering and Metabolism of Doxorubicin Chemotherapy.

Fabris S, MacLean DA - PLoS ONE (2015)

Bottom Line: Doxorubicin remains one of the most widely used chemotherapeutic agents however its effect on healthy tissue, such as skeletal muscle, remains poorly understood.The interstitial space within the muscle did not appear to play a significant rate limiting compartment for the uptake or release of DOX or DOXol from the tissue to the circulation.It appears that the sequestering of drug in skeletal muscle plays an acute and important role in the systemic availability and metabolism of DOX which may have a greater impact on the clinical outcome than previously considered.

View Article: PubMed Central - PubMed

Affiliation: Biomolecular Sciences, Laurentian University, Ontario, Canada.

ABSTRACT
Doxorubicin remains one of the most widely used chemotherapeutic agents however its effect on healthy tissue, such as skeletal muscle, remains poorly understood. The purpose of the current study was to examine the accumulation of doxorubicin (DOX) and its metabolite doxorubicinol (DOXol) in skeletal muscle of the rat up to 8 days after the administration of a 1.5 or 4.5 mg kg-1 i.p. dose. Subsequent to either dose, DOX and DOXol were observed in skeletal muscle throughout the length of the experiment. Interestingly an efflux of DOX was examined after 96 hours, followed by an apparent re-uptake of the drug which coincided with a spike and rapid decrease of plasma DOX concentrations. The interstitial space within the muscle did not appear to play a significant rate limiting compartment for the uptake or release of DOX or DOXol from the tissue to the circulation. Furthermore, there was no evidence that DOX preferentially accumulated in a specific muscle group with either dose. It appears that the sequestering of drug in skeletal muscle plays an acute and important role in the systemic availability and metabolism of DOX which may have a greater impact on the clinical outcome than previously considered.

No MeSH data available.


Doxorubicin (A) and Doxorubicinol (B) concentrations in the interstitial space of skeletal muscle following the IP administration of 1.5 or 4.5 mg kg-1 Doxorubicin.✝ Designates significance compared to baseline for the 1.5 mg kg-1 dose. * Designates significance compared to baseline for the 4.5 mg kg-1 dose.
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pone.0139070.g004: Doxorubicin (A) and Doxorubicinol (B) concentrations in the interstitial space of skeletal muscle following the IP administration of 1.5 or 4.5 mg kg-1 Doxorubicin.✝ Designates significance compared to baseline for the 1.5 mg kg-1 dose. * Designates significance compared to baseline for the 4.5 mg kg-1 dose.

Mentions: Following the 1.5 mg kg-1 dose, interstitial DOX concentrations were measurable (P<0.05) after 48 hours (0.58±0.28 nM) then decreased until 120 hours (0.24±0.1 nM; P<0.05) where levels remained stable for the remainder of the experiment. Similarly, as a result of the 4.5 mg/kg, DOX was measurable (P<0.05) after 48 hours (0.4±0.18 nM) and decreased until 96 hours (0.44±0.18 nM; P<0.05) where concentrations remained stable for the remainder of the experiment. There were no significant differences in interstitial DOX concentrations at any time point when comparing between administered doses (Fig 4A).


Skeletal Muscle an Active Compartment in the Sequestering and Metabolism of Doxorubicin Chemotherapy.

Fabris S, MacLean DA - PLoS ONE (2015)

Doxorubicin (A) and Doxorubicinol (B) concentrations in the interstitial space of skeletal muscle following the IP administration of 1.5 or 4.5 mg kg-1 Doxorubicin.✝ Designates significance compared to baseline for the 1.5 mg kg-1 dose. * Designates significance compared to baseline for the 4.5 mg kg-1 dose.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581622&req=5

pone.0139070.g004: Doxorubicin (A) and Doxorubicinol (B) concentrations in the interstitial space of skeletal muscle following the IP administration of 1.5 or 4.5 mg kg-1 Doxorubicin.✝ Designates significance compared to baseline for the 1.5 mg kg-1 dose. * Designates significance compared to baseline for the 4.5 mg kg-1 dose.
Mentions: Following the 1.5 mg kg-1 dose, interstitial DOX concentrations were measurable (P<0.05) after 48 hours (0.58±0.28 nM) then decreased until 120 hours (0.24±0.1 nM; P<0.05) where levels remained stable for the remainder of the experiment. Similarly, as a result of the 4.5 mg/kg, DOX was measurable (P<0.05) after 48 hours (0.4±0.18 nM) and decreased until 96 hours (0.44±0.18 nM; P<0.05) where concentrations remained stable for the remainder of the experiment. There were no significant differences in interstitial DOX concentrations at any time point when comparing between administered doses (Fig 4A).

Bottom Line: Doxorubicin remains one of the most widely used chemotherapeutic agents however its effect on healthy tissue, such as skeletal muscle, remains poorly understood.The interstitial space within the muscle did not appear to play a significant rate limiting compartment for the uptake or release of DOX or DOXol from the tissue to the circulation.It appears that the sequestering of drug in skeletal muscle plays an acute and important role in the systemic availability and metabolism of DOX which may have a greater impact on the clinical outcome than previously considered.

View Article: PubMed Central - PubMed

Affiliation: Biomolecular Sciences, Laurentian University, Ontario, Canada.

ABSTRACT
Doxorubicin remains one of the most widely used chemotherapeutic agents however its effect on healthy tissue, such as skeletal muscle, remains poorly understood. The purpose of the current study was to examine the accumulation of doxorubicin (DOX) and its metabolite doxorubicinol (DOXol) in skeletal muscle of the rat up to 8 days after the administration of a 1.5 or 4.5 mg kg-1 i.p. dose. Subsequent to either dose, DOX and DOXol were observed in skeletal muscle throughout the length of the experiment. Interestingly an efflux of DOX was examined after 96 hours, followed by an apparent re-uptake of the drug which coincided with a spike and rapid decrease of plasma DOX concentrations. The interstitial space within the muscle did not appear to play a significant rate limiting compartment for the uptake or release of DOX or DOXol from the tissue to the circulation. Furthermore, there was no evidence that DOX preferentially accumulated in a specific muscle group with either dose. It appears that the sequestering of drug in skeletal muscle plays an acute and important role in the systemic availability and metabolism of DOX which may have a greater impact on the clinical outcome than previously considered.

No MeSH data available.