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EFFECT OF HYPERLIPIDEMIA ON DRONEDARONE DISPOSITION

  • Author / Creator
    BIN JARDAN, YOUSEF ABDULLAH M
  • The pharmacokinetics of dronedarone, effect of hyperlipidemia on dronedarone disposition and dronedarone tissue distribution in normolipidemic (NL) and hyperlipidemic (HL) rats were studied. Novel and sensitive HPLC-UV and LC-MS reverse phase assay methods were developed. Rat plasma (100 μL) was subjected to a one-step liquid-liquid extraction followed by separation of the residues after injection into C18 analytical columns. Both methods had excellent linear relationships between peak height ratios and plasma concentrations. The lower limit of quantification of HPLC-UV (dronedarone and desbutyldronedarone) and LC-MS (dronedarone) based on 100 μL of rat plasma were 25 ng/mL and 5 ng/mL, respectively. The HPLC method was then used to characterize the pharmacokinetic profile of dronedarone in the rat. Single doses were administered to rats intravenously (4 mg/kg), orally (55 mg/kg) and intraperitoneally (65 mg/kg). To induce hyperlipidemia (HL), some of the rats to be given oral dronedarone were administered intraperitoneal doses of poloxamer 407 (P407). Dronedarone was found to possess a high volume of distribution and moderate clearance in the rat. The drug showed poor bioavailability (<20%) after oral and intraperitoneal administration. HL increased dronedarone plasma concentrations measured by area under the plasma concentration vs. time curve. Tissue distribution and hepatic microsomal metabolism experiments were conducted to explore the cause of these changes in HL. After oral single doses of dronedarone, rats were anesthetized and plasma and tissue specimens (heart, lung and liver) were collected. Liver and intestinal microsomal proteins from control, P407 and dietary induced obese rats were harvested and used to measure velocity of desbutyldronedarone (metabolite) formation from dronedarone. HL increased the geometric mean area under the concentration vs. time curves of dronedarone by 2.3 to 5-fold. In tissues (heart, liver and lung), however, concentrations of drug selectively increased or decreased. Heart, the site of action of the drug, had the highest levels of dronedarone. Reductions in liver and intestinal metabolic efficiency (intrinsic clearance) were observed in rats with increased serum lipids (P407 and dietary induced obese) rats compared to controls. The data suggested down regulation in enzymes involved in dronedarone metabolism occurs in the presence of increased lipid levels in the serum, which may explain the higher plasma concentrations in rats given P407.

  • Subjects / Keywords
  • Graduation date
    2017-11:Fall 2017
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3J960Q13
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • DION BROCKS
  • Examining committee members and their departments
    • El-Kadi, Ayman (Pharmacy and Pharmaceutical Sciences)
    • Ussher, John (Pharmacy and Pharmaceutical Sciences)
    • Baker, Glen (Psychiatry)
    • Siraki, Arno (Pharmaceutical Sciences)