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The Effects of Elements of Cardiometabolic Syndrome on Metformin Disposition: Obesity and Hyperlipidemia

  • Author / Creator
    Gabr,Raniah Q
  • The influences of obesity, Roux-en-Y gastric bypass bariatric (RYGB) surgery and hyperlipidemia on metformin pharmacokinetics (PK) were investigated. A sensitive and novel HPLC-UV reverse phase assay method was developed and utilized. Detection and mass characterization for metformin metabolites were performed. In a non-blind single dose PK study, 16 post RYGB obese patients and 16 sex and body mass index (BMI) matched control subjects were administered 1000 mg metformin tablet orally, with plasma and urinary metformin levels being measured thereafter. Comparing PK parameters of metformin in surgically untreated obese subjects with healthy subjects in literature, it showed that obesity is associated with a lower metformin clearance, volume of distribution and bioavailability. RYGB surgery seemed to cause a normalization of these parameters. Because the effect of hyperlipidemia (HL) on metformin PK and its PK-dependent transporters (OCT-1, OCT-2 and MATE-1) was unknown, the poloxamer 407 (P407) rodent model of HL was used for assessment. HL was found to not influence the PK of metformin, neither was gene nor transporter protein expression affected. In literature, the ability of metformin to be metabolized is unclear. Although most studies indicated little if any metabolism, a few recent studies suggested substantial metabolism in rats given supratherapeutic doses. Examination of urine samples from rats and human suggested some peaks that might be metabolites of metformin. Using rat hepatocytes there appeared to be chromatographic evidence of metabolite(s). Upon incubation of 100 µg/mL metformin for 30 min with isolated rat microsomes 1 mg protein/mL, we could qualitatively detect the presence of metabolites, one of which coeluted with structurally-similar guanylurea. Fractional separation and mass characterization revealed the presence of mixture of two main masses: one with m/z ratio of 103 which matched guanylurea m/z ratio retention time on HPLC run. The other was with 104.9 m/z ratio which is presumed reduced guanylurea. In conclusion, obesity may affect metformin PK. RYGB has a normalizing effect on metformin PK parameters. P407 model of HL has no effect on metformin related protein transporters PK parameters. Metformin seems to be metabolized only at very high concentrations and supratherapeutic doses.  

  • Subjects / Keywords
  • Graduation date
    2015-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3319SF0W
  • 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)
    • Brocks, Dion (Pharmacy and Pharmaceutical Sciences)
  • Examining committee members and their departments
    • Jurasz, Paul (Pharmacy and Pharmaceutical Sciences)
    • El-Kadi, Ayman (Pharmacy and Pharmaceutical Sciences)
    • Padwal, Raj (Department of Medicine)
    • Ussher, John (Pharmacy and Pharmaceutical Sciences)