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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.


Experimental procedure for microdialysis probe insertion.(A) Exposing the medial and lateral gastrocnemius muscle. (B) Insertion of 21 gauge cannula. (C) Microdialysis probe insertion guided by the cannula. (D) Location of the diffusible membrane within the muscle.
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pone.0139070.g006: Experimental procedure for microdialysis probe insertion.(A) Exposing the medial and lateral gastrocnemius muscle. (B) Insertion of 21 gauge cannula. (C) Microdialysis probe insertion guided by the cannula. (D) Location of the diffusible membrane within the muscle.

Mentions: Using curved dissecting scissors, incisions were made at the base of the leg and the skin was manually pulled back until the entire leg was exposed (Fig 6A) and then the excess skin was removed. A 21 gauge curved cannula was inserted anteriorly into the muscle along the muscle’s natural fibre orientation (Fig 6B) and acted as a guide for the microdialysis probe. Once the cannula was in place, the 9.5 cm portion of the probe is inserted caudally through the cannula and extended past the foot (Fig 6C). As soon as the diffusible portion of the probe was oriented into the muscle, then the 5 cm portion of the probe was held in place while the cannula was retracted out of the tissue leaving the probe in place (Fig 6D).


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

Fabris S, MacLean DA - PLoS ONE (2015)

Experimental procedure for microdialysis probe insertion.(A) Exposing the medial and lateral gastrocnemius muscle. (B) Insertion of 21 gauge cannula. (C) Microdialysis probe insertion guided by the cannula. (D) Location of the diffusible membrane within the muscle.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0139070.g006: Experimental procedure for microdialysis probe insertion.(A) Exposing the medial and lateral gastrocnemius muscle. (B) Insertion of 21 gauge cannula. (C) Microdialysis probe insertion guided by the cannula. (D) Location of the diffusible membrane within the muscle.
Mentions: Using curved dissecting scissors, incisions were made at the base of the leg and the skin was manually pulled back until the entire leg was exposed (Fig 6A) and then the excess skin was removed. A 21 gauge curved cannula was inserted anteriorly into the muscle along the muscle’s natural fibre orientation (Fig 6B) and acted as a guide for the microdialysis probe. Once the cannula was in place, the 9.5 cm portion of the probe is inserted caudally through the cannula and extended past the foot (Fig 6C). As soon as the diffusible portion of the probe was oriented into the muscle, then the 5 cm portion of the probe was held in place while the cannula was retracted out of the tissue leaving the probe in place (Fig 6D).

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.