Limits...
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.


Doxorubicinol concentrations in skeletal muscle groups following the IP administration of (A) 1.5 mg kg-1 or (B) 4.5 mg kg-1 of Doxorubicin.* Denotes significance when compared to baseline for all muscle groups. There are no significant differences between muscle types at any time point in either administered doses.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4581622&req=5

pone.0139070.g003: Doxorubicinol concentrations in skeletal muscle groups following the IP administration of (A) 1.5 mg kg-1 or (B) 4.5 mg kg-1 of Doxorubicin.* Denotes significance when compared to baseline for all muscle groups. There are no significant differences between muscle types at any time point in either administered doses.

Mentions: DOXol was measurable (P<0.05) in the WG after 72, 144 and 192 hours as a result of the administered 1.5 mg kg-1 dose (Fig 3A). The administration of 4.5 mg kg-1 dose resulted in measureable (P<0.05) DOXol concentrations after 48, 72, 120, 144 and 192 hours (Fig 3B).


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

Fabris S, MacLean DA - PLoS ONE (2015)

Doxorubicinol concentrations in skeletal muscle groups following the IP administration of (A) 1.5 mg kg-1 or (B) 4.5 mg kg-1 of Doxorubicin.* Denotes significance when compared to baseline for all muscle groups. There are no significant differences between muscle types at any time point in either administered doses.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0139070.g003: Doxorubicinol concentrations in skeletal muscle groups following the IP administration of (A) 1.5 mg kg-1 or (B) 4.5 mg kg-1 of Doxorubicin.* Denotes significance when compared to baseline for all muscle groups. There are no significant differences between muscle types at any time point in either administered doses.
Mentions: DOXol was measurable (P<0.05) in the WG after 72, 144 and 192 hours as a result of the administered 1.5 mg kg-1 dose (Fig 3A). The administration of 4.5 mg kg-1 dose resulted in measureable (P<0.05) DOXol concentrations after 48, 72, 120, 144 and 192 hours (Fig 3B).

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.