Dataset Information

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 ?g * 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 ?-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.

SUBMITTER: Alrushaid S

PROVIDER: S-EPMC5620576 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative.

Alrushaid Samaa S Sayre Casey L CL Yáñez Jaime A JA Forrest M Laird ML Senadheera Sanjeewa N SN Burczynski Frank J FJ Löbenberg Raimar R Davies Neal M NM

Pharmaceutics 20170913 3

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 administrati ...[more]

PMID: 28902176

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Project description:Objective: To assess the role of aldoketoreductases and other doxorubicin pharmacokinetic or pharmacogenomic genes in doxorubicin cytotoxicity, resistance, DNA binding activity, and subcellular localization, Methods: We conducted a whole genome microarray study to identify differences in between doxorubicin-sensitive MCF-7cc cells and doxorubicin-resistant MCF-7Dox2-12 cells in terms of their expression of genes related to doxorubicin pharmacokinetics or pharmacodynamics. Targets were then validated by pharmacologic inhibition in conjunction with drug metabolite profiling, drug localization, drug cytotoxicity, and drug DNA binding studies. Results: 2063 differentially expressed transcripts were identified, including 17% and 43% of genes or gene families associated with doxorubicin pharmacokinetics or pharmacodynamics (p values of significance of 0.05 and <0.0001, respectively). The largest changes in the expression of genes associated with doxorubicin pharmacokinetics and pharmacodynamics were chiefly among the aldo-keto reductases (AKRs) Akr1c2, Akr1c3 and Akr1b10 which convert doxorubicin to doxorubicinol. We observed that doxorubicinol exhibits dramatically reduced drug toxicity, reduced drug DNA-binding activity, and altered drug subcellular localization to lysosomes. Pharmacologic inhibition of these AKRs in MCF-7Dox2-12 cells restored drug cytotoxicity, and drug localization to the nucleus. Conclusion: These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledgebases to identify highly relevant genes associated with doxorubicin resistance. The products of one or more of these genes could effectively be shown to alter the drug’s properties, while inhibiting them restored drug DNA binding, cytotoxicity, and subcellular localization. Doxorubicin resistant cell lines of breast MCF-7 cells were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with four labelling replicates of both forward and reverse labellings plus another set of 8 arrays with forward labelling. Sixteen arrays were used for this experiments. The co-cultured control cells MCF-7cc12 was generated by parallel selection process in the absence of drug.

Project description:Since proteins involved in chemotherapy drug pharmacokinetics and pharmacodynamics have a strong impact on the uptake, metabolism, and efflux of such drugs, they likely play critical roles in resistance to chemotherapy drugs in cancer patients.To investigate this hypothesis, we conducted a whole genome microarray study to identify difference in the expression of genes between isogenic doxorubicin-sensitive and doxorubicin-resistant MCF-7 breast tumour cells. We then assessed the degree of over-representation of doxorubicin pharmacokinetic and pharmacodynamic genes in the dataset of doxorubicin resistance genes.Of 27,958 Entrez genes on the array, 7.4 per cent or 2,063 genes were differentially expressed by???2-fold between wildtype and doxorubicin-resistant cells. The false discovery rate was set at 0.01 and the minimum p value for significance for any gene within the "hit list" was 0.01. Seventeen and 43 per cent of doxorubicin pharmacokinetic genes were over-represented in the hit list, depending upon whether the gene name was identical or within the same gene family, respectively. The most over-represented genes were within the 1C and 1B families of aldo-keto reductases (AKRs), which convert doxorubicin to doxorubicinol. Other genes convert doxorubicin to other metabolites or affect the influx, efflux, or cytotoxicity of the drug. In further support of the role of AKRs in doxorubicin resistance, we observed that, in comparison to doxorubicin, doxorubincol exhibited dramatically reduced cytotoxicity, reduced DNA-binding activity, and strong localization to extra nuclear lysosomes. Pharmacologic inhibition of the above AKRs in doxorubicin-resistant cells increased cellular doxorubicin levels, restored doxorubicin cytotoxicity and re-established doxorubicin localization to the nucleus. The properties of doxorubicinol were unaffected.These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledge bases to identify highly relevant genes associated with doxorubicin resistance. The induction of one or more of these genes was found to be correlated with changes in the drug's properties, while inhibiting one specific class of these genes (the AKRs) increased cellular doxorubicin content and restored drug DNA binding, cytotoxicity, and subcellular localization.

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Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative.

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Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative.

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