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|Title:||A comparison of doxorubicin and doxorubicinol in rat heart and liver tissue following anthracycline administration|
|Publisher:||Laurentian University of Sudbury|
|Abstract:||This study examined the pharmacokinetic profile of the chemotherapeutic drug doxorubicin (DOX), and of its main metabolite doxorubicinol (DOXOL) in male Sprague-Dawley rats. HPLC was used to evaluate both the effect of dose (1.5 mg/kg vs. 4.5 mg/kg) and the effect of recovery time (24, 24, 72, 96, 120, 144, 168 and 192 hours) from the bolus intraperitoneal injection on plasma, liver and heart concentrations. Fluorescence microscopy allowed for qualitative analysis of DOX in liver and heart sections. Plasma concentrations of both drug and metabolite were relatively stable over the examination period. The pattern of response was similar in the liver, although DOX concentrations were decreased after 192 hours, preceded by a spike in DOXOL at 168 hours. The 4.5 mg/kg dose produced increased concentrations of DOX at several of the initial sampling time points in this tissue. In heart tissue, concentrations of DOX steadily decreased for both doses and a dose response was evident until 144 hours. No differences were distinguishable between time-points nor between doses beyond 144 hours. The concentration of DOXOL in this tissue was elevated after 24 hours and subsequently remained stable. Interestingly, DOX and DOXOL remained detectable at 192 hours post-injection for all samples. Fluorescence microscopy results consistently revealed sections that indicated the presence of DOX and were representative of the tissues being analyzed. It was observed that following injection, DOX entered the nuclei of cells rather rapidly and seemingly in proportion to the dose administered. This localization was less apparent as time progressed. These findings strongly suggest that DOX was rapidly absorbed, distributed and metabolized, however its elimination patterns remain unclear. The fact that concentrations remained relatively stable in plasma and liver, and fixed in heart tissue after 144 hours, implies that it is stored in cardiac iii tissue, and also potentially in other compartments, allowing for constant re-introduction and re-distribution. Remarkably, an increase in the dose administered did not produce greater accumulation of either drug or metabolite over time in any of the tissues analyzed, therefore the mechanism(s) responsible for the uptake and distribution within the tissues appear to be rate limiting (dose-independent). Nevertheless, the residual amounts of DOX and DOXOL in the heart and liver suggest the possibility of further accumulation upon repeated injections, supporting previous findings suggesting that cumulative doses of DOX are extremely damaging and can result in cardioxicity.|
|Appears in Collections:||Master's Theses|
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