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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 arterial plasma following the IP administration of 1.5 or 4.5 mg kg-1 Doxorubicin.(A) Significance compared to baseline for the 1.5 mg kg-1 dose is denoted by ✝ and 4.5 mg kg-1 by *. α Denotes an increase (P<0.05) compared to 24, 48, 72, 120, 144 and 168 hours as a result of the 1.5 mg kg-1 dose. β Denotes difference (P<0.05) between administered doses. (B) Significance compared to baseline for the 1.5 mg kg-1 dose is denoted by ✝ and 4.5 mg kg-1 by *. α Denotes a decrease (P<0.05) compared to 24 hours. β Denotes difference (P<0.05) between administered doses.
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pone.0139070.g001: Doxorubicin (A) and Doxorubicinol (B) concentrations in the arterial plasma following the IP administration of 1.5 or 4.5 mg kg-1 Doxorubicin.(A) Significance compared to baseline for the 1.5 mg kg-1 dose is denoted by ✝ and 4.5 mg kg-1 by *. α Denotes an increase (P<0.05) compared to 24, 48, 72, 120, 144 and 168 hours as a result of the 1.5 mg kg-1 dose. β Denotes difference (P<0.05) between administered doses. (B) Significance compared to baseline for the 1.5 mg kg-1 dose is denoted by ✝ and 4.5 mg kg-1 by *. α Denotes a decrease (P<0.05) compared to 24 hours. β Denotes difference (P<0.05) between administered doses.

Mentions: The administration of 1.5 mg kg-1 DOX elevated (P<0.05) arterial concentrations of DOX throughout the experiment, with the highest concentration observed after 96 (41.4±17.9 nM) and 192 hours (20.3±7.5 nM) post injection as compared to baseline. Similarly, circulating concentrations were elevated (P<0.05) throughout the experiment following the administration of 4.5 mg kg-1 DOX. When compared to the 1.5 mg kg-1 dose, the concentration of DOX was greater (P<0.05) following the 4.5 mg kg-1 dose after 24 (300±77%), 72 (609±119%), 120 (288±0%) and 144 (845±147%) hours (Fig 1A).


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 arterial plasma following the IP administration of 1.5 or 4.5 mg kg-1 Doxorubicin.(A) Significance compared to baseline for the 1.5 mg kg-1 dose is denoted by ✝ and 4.5 mg kg-1 by *. α Denotes an increase (P<0.05) compared to 24, 48, 72, 120, 144 and 168 hours as a result of the 1.5 mg kg-1 dose. β Denotes difference (P<0.05) between administered doses. (B) Significance compared to baseline for the 1.5 mg kg-1 dose is denoted by ✝ and 4.5 mg kg-1 by *. α Denotes a decrease (P<0.05) compared to 24 hours. β Denotes difference (P<0.05) between administered doses.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4581622&req=5

pone.0139070.g001: Doxorubicin (A) and Doxorubicinol (B) concentrations in the arterial plasma following the IP administration of 1.5 or 4.5 mg kg-1 Doxorubicin.(A) Significance compared to baseline for the 1.5 mg kg-1 dose is denoted by ✝ and 4.5 mg kg-1 by *. α Denotes an increase (P<0.05) compared to 24, 48, 72, 120, 144 and 168 hours as a result of the 1.5 mg kg-1 dose. β Denotes difference (P<0.05) between administered doses. (B) Significance compared to baseline for the 1.5 mg kg-1 dose is denoted by ✝ and 4.5 mg kg-1 by *. α Denotes a decrease (P<0.05) compared to 24 hours. β Denotes difference (P<0.05) between administered doses.
Mentions: The administration of 1.5 mg kg-1 DOX elevated (P<0.05) arterial concentrations of DOX throughout the experiment, with the highest concentration observed after 96 (41.4±17.9 nM) and 192 hours (20.3±7.5 nM) post injection as compared to baseline. Similarly, circulating concentrations were elevated (P<0.05) throughout the experiment following the administration of 4.5 mg kg-1 DOX. When compared to the 1.5 mg kg-1 dose, the concentration of DOX was greater (P<0.05) following the 4.5 mg kg-1 dose after 24 (300±77%), 72 (609±119%), 120 (288±0%) and 144 (845±147%) hours (Fig 1A).

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.