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Impact of Obesity on Metabolism of Some Selected Anesthetic Agents

  • Author / Creator
    Al Nebaihi, Hamdah
  • Over the last few decades the incidence of obesity has increased remarkably in Canada and in the rest of the world, with the highest increases occurring in the excessive weight categories class II (BMI 35– 39.9) and class III (BMI ≥ 40). By 2019, it is anticipated that over 20% of the Canadian adult population will be obese. Obese patients pose significant challenges to anesthesiologists in terms of dose accuracy of anesthetics due to potentially altered pharmacokinetics. In our research project, we aim to investigate the influence of obesity on the proteins level of drug metabolizing enzymes as well as the drug pharmacokinetics parameters of propofol and lidocaine which are commonly used drugs for the induction and maintenance of general and local anesthesia. In addition, we aim to assess the impact of obesity on drug metabolizing enzymes after high fat feedings, and after a switch back to a normal diet. For lidocaine study, male and female rats (n=8 for each group) were fed high fat diet (HF) for 14 weeks. At the end of 14 weeks period, half of each male and female group were euthanized. In the remaining rats, the diet was switched to standard rat chow. Four weeks after, those rats were euthanized. For each 14 & 18 week groups, control rats (n=4 each) were fed standard chow. Afterwards, we investigated the impact of obesity on the activity of phase I drug metabolizing enzymes using lidocaine as well as the protein contents of cytochrome P450 (CYP) enzymes in female rats. What we found is that after 14 weeks on high fat diet, MEGX (lidocaine active metabolite) maximum formation rate was reduced significantly. Moreover, Expressions of CYP3A1, CYP1A2, and CYP2C12 were also significantly lower compared to control group. Interestingly, the expressions were returned to normal levels when the normal diet was implemented from weeks 14 to 18. We also examined the influence of obesity on phase II enzymes using propofol as well as the protein expression of UGT1A1 (phase II) and CYP2D1 (phase I). In this part of the experiment, the animal model comprised male rats fed 14 weeks of either standard (normal) chow with water (control), 45% high fat chow (HF) and water, normal chow with high fructose corn syrup water (HFCS), and HFCS and HF combined. After 14 weeks on high caloric diet, hepatic microsomal rate of glucuronidation of propofol was significantly low in HF group while HFCS and HFCS+HF showed the opposite effect on glucuronidation activity. Diet rich in fat led to a reduction in the activity of UGT1A1 and CYP2D1.Our findings indicate that diet-induced obesity was associated with a reduction in the hepatic microsomal rates of MEGX formation and expression of some metabolizing enzymes. The hepatic microsomal rate of glucuronidation demonstrated a different trend in the enzyme activities with different diet (HF, HFCS, and HF+HFCS). Reduction in the fat content of the diet reversed the changes in CYP expression.

  • Subjects / Keywords
  • Graduation date
    2019-06
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/r3-bc3j-pc90
  • License
    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. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. 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.