Determination of relationship between dolutegravir and trace amine profile, using advanced liquid chromatography tandem mass spectrometry analysis of various tissues

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dc.contributor.advisorSmith, Carineen_ZA
dc.contributor.advisorKellermann, Tracyen_ZA
dc.contributor.authorHenning, Natashaen_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Dept. of Medicine. Division of Clinical Pharmacology.en_ZA
dc.date.accessioned2023-09-08T13:46:14Zen_ZA
dc.date.accessioned2024-01-08T12:32:25Zen_ZA
dc.date.available2023-09-08T13:46:14Zen_ZA
dc.date.available2024-01-08T12:32:25Zen_ZA
dc.date.issued2023-12en_ZA
dc.descriptionThesis (PhD)--Stellenbosch University, 2023.en_ZA
dc.description.abstractENGLISH 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.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Die immunopatogeniese meganismes van menslike immuniteitsvirus is geweldig ingewikkeld en vereis ‘n multidismensionele benadering tot farmakologiese behandeling. Huidige antiretrovirale behandeling bestaan uit kombinasie terapie wat dikwels aanleiding gee tot ongewensde newe-effekte, maar die meganismes wat lei tot hierdie newe-effekte is nog onbekend, veral in die geval van dolutegravir (DTG) – ‘n integrase inhibeerder - wat tans deel vorm van die eerste linie antiretrovirale middels op die mark. Die mees onlangse literatuur stel voor dat die neurologiese en die spysverterings newe-effekte veroorsaak word deur die opeenhoping van DTG in verskillende weefselkompartemente – ‘n hipotese wat ondersteun word deur die middel se fisies-chemiese eienskappe. Steeds is daar bitter min literatuur beskikbaar wat metodes voorstel om DTG-opeenhoping in weefsel te ondersoek. Spoor-amiene is biogeniese amiene wat in klein hoeveelhede in die brein vervaardig word. Die ermmikrobioom dra ook intussen by tot die vervaardiging van die spooramiene - in merkbaar groter hoeveelhede. Spoor-amiene word gekenmerk vir die rol wat dit speel in die modulering van ‘n verskeidenheid inflammatoriese uitkomste. Daarom het ons voorgestel dat die moonlike wanregulering van die spooramienergiese stelsel weens DTG toediening, potensieel mag bydra tot die voortdurende inflammasie wat met MIV geassosieer word. Om die moontlike impak van DTG toediening aan die spoor-amienergiese stelsel te ondersoek, was ‘n multidissiplinêre benadering nodig. Daarom is ‘n in vivo wistar rot model en vloeistofchromatografie-massaspektofrafie metode gekombineer om die konsentrasies van DTG en verskillende spoor amine in weefsel akkuraat vas te stel. Die data wat tydens die studie gegenereer is, illustreer dat kroniese DTG behandeling - wat monoterapie in mense naboots – lei tot opeenhoping van DTG in verskillende weefsel. Verder dra die DTG by tot veranderinge in die urine en spysverteringskanaal spoor-amienprofiel van wistar rotte. In lyn met groter voorkoms van newe-effecte in vroulike pasiënte, wys DTG bepaling in weefsels dat DTG konsentrasies beduidend hoër was in vroulike diere as in manlike diere. In lyn hiermee, was daar ‘n direkte verhouding tussen DTG plasmakonsentrasies en DTG konsentrasies in spier en lewer (maar nie vetweefsel nie). Gegewe die feit dat DTG wel in weefsel opgehoop het, is verdere analitiese ondersoeke ingestel om die moontlike effek van DTG op die spoor-amienprofiel te bepaal. Modulering van die spoor-amienprofiel was inderdaad veranderd na DTG toediening, met ʼn bykomende effek van geslag . Ten slotte, hierdie proefskrif by tot ons begrip aan die verskillende meganismes wat moontlik bydrae tot die inflammasie gesentreerde newe-effekte wat volg na DTG behandeling. Huidige data lê ook klem op die feit dat beide manlike en vroulike geslagte in toekomstige studies ingesluit moet word. Vanuit ‘n kliniese perspektief beklemtoon data die belangrikheid van meer akkurate aanpassings aan dosis van DTG om die risiko van oordosering (moontlik die oorsaak van die newe-effekte opgemerk) tot ‘n minimum te beperk in vroue en/of persone met relatief Kleiner liggaamsbou.af_ZA
dc.description.versionDoctorateen_ZA
dc.format.extentviii, 186 pages : illustrationsen_ZA
dc.identifier.urihttps://scholar.sun.ac.za/handle/10019.1/128826en_ZA
dc.language.isoen_ZAen_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subject.lcshHIV (Viruses) -- Treatment -- Complicationsen_ZA
dc.subject.lcshAntiretroviral agents -- Side effectsen_ZA
dc.subject.lcshDolutegravir en_ZA
dc.subject.lcshTrace amine systemen_ZA
dc.titleDetermination of relationship between dolutegravir and trace amine profile, using advanced liquid chromatography tandem mass spectrometry analysis of various tissuesen_ZA
dc.typeThesisen_ZA
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