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Skeletal muscle as a possible compartment for the sequestering of Doxorubicin following administration
Author(s) -
Fabris Sergio Antonio,
Chenard Pamela,
MacLean David
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb784
Subject(s) - skeletal muscle , doxorubicin , intramuscular injection , chemistry , bolus (digestion) , pharmacokinetics , gastrocnemius muscle , medicine , pharmacology , intravenous bolus , endocrinology , chemotherapy
Doxorubicin (DOX) is an anti‐cancer chemotherapeutic and although widely used, its accumulation over time in skeletal muscle tissue has attracted little attention. The purpose of this research was to study intracellular DOX concentrations in skeletal muscle following its administration in the rat. A bolus injection of 1.5 and 4.5 mg/kg of DOX was administered intraperitoneally in Sprague Dawley rats, and medial gastrocnemius samples were collected 24 and 96 hrs post injection. Intramuscular DOX concentrations were elevated (P<0.05) as compared to control at all time points. Following the 1.5 and 4.5 mg/kg dose, intramuscular concentrations decreased (P<0.05) from 0.24±0.05 and 0.83±0.18 nmol/g at 24 hrs to 0.04±0.01 and 0.40±0.10 nmol/g at 96 hrs, respectively. Although there was a decrease in the intramuscular concentration of DOX over time, these levels remained higher (P<0.05) in the 4.5 mg/kg rats as compared to those administered the 1.5 mg/kg dose. Interestingly, at the lower dose, the intramuscular DOX levels had decreased 83% between 24–96 hrs, while at the larger dose this decrease was only 52%. These data clearly demonstrate that DOX accumulates in skeletal muscle in a dose dependant manner. Furthermore, it appears that the rate of removal or degradation of the intramuscular DOX is slower at increasing doses. These findings have clinical implications as skeletal muscle may be an important compartment for the sequestering of DOX from the circulation, hence limiting its therapeutic impact. This intramuscular accumulation may also have an effect on long‐term function as its metabolite has been shown to be cytotoxic. Supported by NSERC.