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Pharmaceutics 2017, 9(3), 35;

Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative

College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
College of Pharmacy, Roseman University of Health Sciences, South Jordan, UT 84096, USA
YARI International Group, New Brunswick, NJ 08901 and INDETEC Corp., Lima, Peru
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada
Author to whom correspondence should be addressed.
Received: 9 July 2017 / Revised: 11 September 2017 / Accepted: 11 September 2017 / Published: 13 September 2017
(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)
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Doxorubicin (Dox) is an effective anti-cancer medication with poor oral bioavailability and systemic toxicities. DoxQ was developed by conjugating Dox to the lymphatically absorbed antioxidant quercetin to improve Dox’s bioavailability and tolerability. The purpose of this study was to characterize the pharmacokinetics and safety of Dox after intravenous (IV) and oral (PO) administration of DoxQ or Dox (10 mg/kg) and investigate the intestinal lymphatic delivery of Dox after PO DoxQ administration in male Sprague–Dawley rats. Drug concentrations in serum, urine, and lymph were quantified by HPLC with fluorescence detection. DoxQ intact IV showed a 5-fold increase in the area under the curve (AUC)—18.6 ± 1.98 compared to 3.97 ± 0.71 μg * h/mL after Dox—and a significant reduction in the volume of distribution (Vss): 0.138 ± 0.015 versus 6.35 ± 1.06 L/kg. The fraction excreted unchanged in urine (fe) of IV DoxQ and Dox was ~5% and ~11%, respectively. Cumulative amounts of Dox in the mesenteric lymph fluid after oral DoxQ were twice as high as Dox in a mesenteric lymph duct cannulation rat model. Oral DoxQ increased AUC of Dox by ~1.5-fold compared to after oral Dox. Concentrations of β-N-Acetylglucosaminidase (NAG) but not cardiac troponin (cTnI) were lower after IV DoxQ than Dox. DoxQ altered the pharmacokinetic disposition of Dox, improved its renal safety and oral bioavailability, and is in part transported through intestinal lymphatics. View Full-Text
Keywords: doxorubicin; quercetin; pharmacokinetics; bioavailability; lymphatics transport; toxicity doxorubicin; quercetin; pharmacokinetics; bioavailability; lymphatics transport; toxicity

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Alrushaid, S.; Sayre, C.L.; Yáñez, J.A.; Forrest, M.L.; Senadheera, S.N.; Burczynski, F.J.; Löbenberg, R.; Davies, N.M. Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative. Pharmaceutics 2017, 9, 35.

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