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

Descriptions

Other title
Subject/Keyword
Hyperlipidemia
Obesity
Metformin
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Gabr,Raniah Q
Supervisor and department
Brocks, Dion (Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Jurasz, Paul (Pharmacy and Pharmaceutical Sciences)
Ussher, John (Pharmacy and Pharmaceutical Sciences)
El-Kadi, Ayman (Pharmacy and Pharmaceutical Sciences)
Padwal, Raj (Department of Medicine)
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization
Pharmaceutical Sciences
Date accepted
2015-09-17T14:43:16Z
Graduation date
2015-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.  
Language
English
DOI
doi:10.7939/R3319SF0W
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Padwal RS, Gabr RQ, Sharma AM, Langkaas LA, Birch DW, Karmali S, Brocks DR, “Effect of gastric bypass surgery on the absorption and bioavailability of metformin. Diabetes Care journal, 2011, vol. 34, issue 6, 1295-300.Gabr RQ, Padwal RS, Brocks DR, “Determination of metformin in human plasma and urine by high-performance liquid chromatography using small sample volume and conventional octadecyl silane column. Journal of Pharmacy and Pharmaceutical Sciences 2010, vol. 13,486–494

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