Doxorubicin (Dox) is an effective anti-cancer medication with poor oral bioavailability\nand systemic toxicities. DoxQ was developed by conjugating Dox to the lymphatically absorbed\nantioxidant quercetin to improve Doxââ?¬â?¢s bioavailability and tolerability. The purpose of this study\nwas to characterize the pharmacokinetics and safety of Dox after intravenous (IV) and oral (PO)\nadministration of DoxQ or Dox (10 mg/kg) and investigate the intestinal lymphatic delivery of\nDox after PO DoxQ administration in male Spragueââ?¬â??Dawley rats. Drug concentrations in serum,\nurine, and lymph were quantified by HPLC with fluorescence detection. DoxQ intact IV showed a\n5-fold increase in the area under the curve (AUC)ââ?¬â?18.6 1.98 compared to 3.97 0.71 g * h/mL\nafter Doxââ?¬â?and a significant reduction in the volume of distribution (Vss): 0.138 0.015 versus\n6.35 1.06 L/kg. The fraction excreted unchanged in urine (fe) of IV DoxQ and Dox was ~5% and\n~11%, respectively. Cumulative amounts of Dox in the mesenteric lymph fluid after oral DoxQ\nwere twice as high as Dox in a mesenteric lymph duct cannulation rat model. Oral DoxQ increased\nAUC of Dox by ~1.5-fold compared to after oral Dox. Concentrations of -N-Acetylglucosaminidase\n(NAG) but not cardiac troponin (cTnI) were lower after IV DoxQ than Dox. DoxQ altered the\npharmacokinetic disposition of Dox, improved its renal safety and oral bioavailability, and is in part\ntransported through intestinal lymphatics.
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