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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.


Organization of experimental groups and experimental procedures.(A) Schematic representation of the experimental groups receiving an injection of 1.5 mg kg-1 dose (groups 1–8) or 4.5 mg kg-1 (groups 9–16) of DOX IP. A sham injection is administered to the control group (Ctrl). (B) Representation of the experimental proceedings for dialysate, blood and tissue collection following microdialysis probe insertion and carotid artery cannulation.
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pone.0139070.g005: Organization of experimental groups and experimental procedures.(A) Schematic representation of the experimental groups receiving an injection of 1.5 mg kg-1 dose (groups 1–8) or 4.5 mg kg-1 (groups 9–16) of DOX IP. A sham injection is administered to the control group (Ctrl). (B) Representation of the experimental proceedings for dialysate, blood and tissue collection following microdialysis probe insertion and carotid artery cannulation.

Mentions: Rats were injected with Doxorubicin (Doxorubicin Hydrochloride. Pfizer, Canada) at a dose of 1.5 mg kg-1 (Group 1 to 8) or 4.5 mg kg-1 (Group 9 to 16), administered intraperitoneally (IP). A sham injection of saline solution was administered to a control group (IP, n = 6). Once administered, rats were randomly grouped into experimental endpoints (n = 6) of 24, 48, 72, 96, 120, 144, 168 or 192 hours post-injection (Fig 5A). This dose was selected in order to examine the acute effects of the drug on skeletal muscle while minimizing the potential for cardiotoxicity.


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

Fabris S, MacLean DA - PLoS ONE (2015)

Organization of experimental groups and experimental procedures.(A) Schematic representation of the experimental groups receiving an injection of 1.5 mg kg-1 dose (groups 1–8) or 4.5 mg kg-1 (groups 9–16) of DOX IP. A sham injection is administered to the control group (Ctrl). (B) Representation of the experimental proceedings for dialysate, blood and tissue collection following microdialysis probe insertion and carotid artery cannulation.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0139070.g005: Organization of experimental groups and experimental procedures.(A) Schematic representation of the experimental groups receiving an injection of 1.5 mg kg-1 dose (groups 1–8) or 4.5 mg kg-1 (groups 9–16) of DOX IP. A sham injection is administered to the control group (Ctrl). (B) Representation of the experimental proceedings for dialysate, blood and tissue collection following microdialysis probe insertion and carotid artery cannulation.
Mentions: Rats were injected with Doxorubicin (Doxorubicin Hydrochloride. Pfizer, Canada) at a dose of 1.5 mg kg-1 (Group 1 to 8) or 4.5 mg kg-1 (Group 9 to 16), administered intraperitoneally (IP). A sham injection of saline solution was administered to a control group (IP, n = 6). Once administered, rats were randomly grouped into experimental endpoints (n = 6) of 24, 48, 72, 96, 120, 144, 168 or 192 hours post-injection (Fig 5A). This dose was selected in order to examine the acute effects of the drug on skeletal muscle while minimizing the potential for cardiotoxicity.

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.