Doctoral Degrees (Clinical Pharmacology)

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Browsing Doctoral Degrees (Clinical Pharmacology) by browse.metadata.advisor "Smith, Carine"

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    Determination of relationship between dolutegravir and trace amine profile, using advanced liquid chromatography tandem mass spectrometry analysis of various tissues
    (Stellenbosch : Stellenbosch University, 2023-12) Henning, Natasha; Smith, Carine; Kellermann, Tracy; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Dept. of Medicine. Division of Clinical Pharmacology.
    ENGLISH ABSTRACT: The immunopathogenic mechanisms of human immunodeficiency virus (HIV) are complex and require a multidimensional approach to pharmacological management. While it is known that antiretroviral therapy (ART) comprising of multi-drug treatment regimens often lead to the presentation of adverse effects, mechanisms leading to adverse effects require more elucidation. This is especially true for dolutegravir (DTG) – an integrase strand inhibitor (INSTI) – currently part of the first line treatment for HIV. Recent literature has elucidated that the neurological and gastrointestinal adverse events could be related to accumulation of DTG in these tissue compartments because of its physiochemical properties. However, few reports are available for methodology to assess DTG accumulation at tissue levels. Trace amines are biogenic amines which are endogenously produced in trace amounts in the brain, as well as in larger amounts by the gut microbiome and are known to differentially regulate inflammatory outcome. We proposed that a dysregulated trace amine profile may exacerbate the persistent inflammation associated with HIV in both neuronal and gastrointestinal tissue in response to DTG treatment. To elucidate the potential impact of DTG administration on the trace aminergic system, a multidisciplinary approach was required. Therefore, a wistar rat model and novel liquid chromatography tandem mass spectrometry methodology was combined to accurately determine both tissue DTG and trace amine concentrations. Following this approach, data generated illustrated that DTG indeed accumulated in tissue following a chronic DTG dosing regimen which mimics human monotherapy. In addition, DTG altered the urinary and gastrointestinal trace amine profile of wistar rats. In line with higher adverse event reporting by female patients, DTG quantification in plasma and various tissue matrices illustrated significantly higher DTG concentration in female rats when compared to males. In addition, there was a direct relationship between concentrations of DTG in plasma vs concentrations observed in muscle and liver, but not adipose tissue. Since DTG accumulated in tissue, further analytical assessments were conducted to determine potential dysregulation of the trace amine profile by DTG. Data suggest modulation of the trace amine profile by DTG administration, with confounding effect of sex. In conclusion, this dissertation contributes to available literature aimed at elucidating potential mechanisms causing inflammation-centred adverse events following DTG treatment. Data presented illustrate the importance of including both males and females in experimental pharmacology studies. From a clinical perspective, the data presented highlight the importance of more accurate dosage adjustment for body size and/or sex, to minimize risk of over-dosing individuals with relatively smaller body size.