Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative

Abstract

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.

DOX-Vit D, a Novel Doxorubicin Delivery Approach, Inhibits Human Osteosarcoma Cell Proliferation by Inducing Apoptosis While Inhibiting Akt and mTOR Signaling Pathways

“…Given that the main purpose of the current study is to improve the lipopilicity of DOX, we investigated the physiochemical properties of DOX-Vit D in comparison to DOX using ACD iLab and VCCLAB software ( ) as described previously [ 27 ]. Perhaps the better predictor of lipophilicity is the distribution coefficient at pH 7.4 (LogD 7.4 ) since it considers the ionizable group at certain pH in addition to the estimated partition coefficient (Log P ).…”

Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape—A Summary of This Indispensable Special Issue

“…Davies, Lobenberg, Burczynski, and colleagues from the University of Manitoba and Alberta with international collaborators completed a pharmacokinetic analysis of an oral multicomponent joint dietary supplement in dogs as well as a pharmacokinetic and toxicodynamic characterization of a new doxorubicin derivative with reported lymphatic delivery [ 12 ]. Sitar and colleagues from the University of Manitoba and University of Toronto investigated a new theophylline metabolite, theophylline-7β- d -ribofuranoside (theonosine), generated in human and animal lung tissue [ 13 ].…”

Antitumour Anthracyclines: Progress and Perspectives

“…The results revealed the conjugate permits higher intestinal transportation of doxorubicin via lymphatics and its bioavailability and safety were augmented with lower renal toxicity. Despite this, the cardiotoxicity assays, involving specific biomarker (cTnI), showed no relevant difference between doxorubicin and the corresponding conjugate 27 …”