Browsing by Subject "Drug metabolism"

Now showing 1 - 4 of 4
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    The effect of obesity and high fat diet on cardiovascular risk and intestinal drug metabolism
    (2015-01) Tam, Harrison Kin Chi
    Introduction: Childhood obesity is a major epidemic for many industrialized countries, especially in countries where a high fat diet is prevalent. The purpose of this thesis was to examine the effect of obesity and high fat diet on cardiovascular risk factors (e.g. xanthine oxidase activity and uric acid formation) and on small intestinal drug metabolism. Methods: An assay measuring the production of 7-hydroxy-lumazine was developed as a probe for xanthine oxidase activity. This lumazine assay was used to study xanthine oxidase as a risk factor for cardiovascular disease in obese children compared to normal-weight children, and this assay was also utilized to study xanthine oxidase activity in obese adolescents before and after weight loss to determine xanthine oxidase's role in mediating changes in blood pressure due to weight loss. In order to study the effects of obesity and high fat diet on small intestinal drug metabolism, UGT activity was assessed in a rat model of diet-induced obesity using in vitro phenotyping methodologies. Results: Plasma xanthine oxidase activity was increased in obese children and was associated with BMI z-score and waist circumference, but was not associated with blood pressure. Weight loss via meal replacement therapy led to decreases in both uric acid production and excretion, but no significant change in plasma levels. Increases in UGT activity were observed in both obesity resistant and obesity prone rats when they were fed a high fat diet, even though the obesity resistant rats didn't gain a significant amount of weight when fed a high fat diet. Conclusions: Changes in xanthine oxidase activity and intestinal UGT activity may be due to changes to diets and gut microbiota. High fat diets have been shown to alter the gut microbiota and increase plasma LPS levels. Therefore, a high fat diet and not obesity may be responsible for both the changes in xanthine oxidase and UGT activities, and future studies on obesity and CVD risk or alterations in drug metabolizing enzymes should focus on monitoring diets and changes to the gut microbiota.
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    Effect of obesity on hepatic drug metabolism
    (2013-09) Chiney, Manoj Shriram
    Obesity has increased markedly over the last few decades and is now a major public health crisis in the U.S. affecting over 1/3 of the US population. Optimization of dosing in obese individuals is a challenge due to the lack of knowledge regarding changes in the pharmacokinetics (PK) of therapeutic agents in obese individuals. Thus the aim of this thesis was to determine the effect of obesity on drug metabolism and evaluate methods that could potentially predict changes in pharmacokinetics in the obese population. The impact of obesity on drug metabolism in children has not been determined and our clinical study (Chapter 2) was the first of its kind to examine the effect of childhood obesity on CYP1A2, CYP2D6, CYP3A4, xanthine oxidase, and NAT2 activity using caffeine and dextromethorphan as probe drugs. Our results conclusively indicate that obesity results in an elevation of xanthine oxidase and NAT2 enzyme activities in obese children as compared to lean children, whereas there was no difference in CYP1A2, CYP2D6 and CYP3A4 activity between obese and lean children. This study provides a potential mechanism of altered 6-mercaptopurine exposure in the obese pediatric cancer population. While clinical studies would provide the most optimum method to predict clearance of therapeutic agents in humans, studies have reported that clearance can also be predicted using animal data. In Chapter 3, we examined mouse, rat and porcine model of obesity in order to determine the utility of these animal models to predict PK in obese humans and to identify a model that would best reflect the human obesity mediated changes in drug metabolism. The study indicated species dependent differences in CLint of various drugs that were due to, either changes in expression of drug metabolizing enzymes or changes in enzyme substrate affinity. The study demonstrated that obesity can alter enzyme activity in a species and model dependent manner. Furthermore this study identified that the rat High Fat Diet animal model of obesity is the best representation of the obesity mediated alterations in humans. In Chapter 4, in collaboration with Drs. Scott Rector and Jim Perfield, University of Missouri, Columbia, we demonstrated obesity mediated alterations of drug metabolism enzyme activity can be prevented by sterculic oil dietary supplementation. These effects are mediated through signal transduction pathways which regulate CAR and PXR transcription factors. These results establish that obesity mediated changes are biochemically dependent and not weight dependent. In Chapter 5, we developed a proof of concept that would help generate biochemically obese hepatocytes. In absence of hepatocytes from obese individuals, these hepatocytes can be used as a tool to predict obesity mediated changes in drug clearance. Our studies indicate that individually, leptin, resistin, IL-6 and TNF-α can modulate expression of various DMEs in a concentration dependent and isoform specific manner. This study demonstrates that the obesity microenvironment is important in obesity mediated changes in drug metabolism. Additional studies would help establish a more robust method to generate and validate these obese hepatocytes. In summary, the work in this thesis has helped identify the drug metabolism enzymes that are altered in the obese children, the utility of using animal models of obesity as tools to study the impact of obesity on pharmacokinetics/pharmacodynamics, proven that it is possible to reverse obesity mediated changes in drug metabolism and developed an in vitro model that may be used to predict changes in drug disposition in the obese population. These findings are important for to better develop dosing strategies in obese humans with concomitant disease.
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    Investigating the Effects of Antidepressants on Intestinal Bacteria
    (2024-04-16) Lebakken, Sophia; Basting, Christopher M; Bailey, Melisa; Schroeder, Ty; Broedlow, Courtney A; Guerrero, Candace; Hemmila, Charlotte; Klatt, Nichole R
    Introduction: The gut-brain axis (GBA) involves bidirectional communication between the gastrointestinal tract and brain, which contains many species of bacteria that play an important role in this communication. Major depressive disorder is often treated with antidepressant medications (ADMs) that pass through the gastrointestinal tract; however, the possible adverse effects of ADMs on the gut microbiome are not well characterized. Methods: This project investigates the impact of three selective serotonin reuptake inhibitors, sertraline, fluoxetine, citalopram; one norepinephrine and dopamine reuptake inhibitor, bupropion; and one tetracyclic antidepressant, mirtazapine, on the growth of eight species of gut bacteria, Bacteroides fragilis, Bifidobacterium longum, Bacteroides uniformis, Collinsella aerofaciens, Prevotella copri, Escherichia coli, Akkermansia muciniphila, and Lactobacillus plantarum. Bacteria were treated with various concentrations of each ADM to determine potential impact on growth. We calculated the concentration of drug needed to inhibit growth by 50% (IC50) using spectrophotometry. Results Several ADMs inhibited gut bacterial growth. At 50% bacterial growth inhibition, the most prominent was sertraline (28.742 μM), followed by bupropion (43.976 μM), then fluoxetine (76.449 μM). Citalopram (244.738 μM) and mirtazapine (294.316 μM) exhibited far less inhibition. Discussion These findings suggest ADMs have antibiotic effects that disturb the microbiome resulting in potential consequences for microbiota-GBA interactions. Building on these results, future experimentation will measure uptake and metabolism of ADMs by exposing bacteria to each drug longitudinally. Metabolites will be characterized using liquid chromatography-mass spectrometry. Conclusion Given the profound impact of the gut microbiome on the gut-brain axis, these data provide novel insights into potential mechanisms by which ADMs could have unintended consequences on the gut that may perpetuate, instead of treat, mood disorders thus the microbiome should be further investigated in relation to ADMs.
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    Metabolism and CNS Distribution of Selected Histone Deacetylase Inhibitors
    (2024-03) Zhang, Wenqiu
    Brain tumors are the leading cause of cancer-related death in children and efficacious treatment remains a critical unmet need. The blood-brain barrier (BBB) is a major hurdle for effective delivery of treatments for tumors in the central nervous system (CNS). While the paracellular transport of large, hydrophilic molecules is largely limited by tight junctions, efflux transporter systems are a key element of the BBB that can limit the penetration of lipophilic drugs. Histone deacetylase inhibitors (HDACIs) have been widely explored for their application in oncology, including the field of neuro-oncology. Despite their high in vitro potency and CNS-penetration-favorable physicochemical properties, the in vivo efficacy of HDACIs has been poor for CNS tumor treatment. This lack of in vitro-in vivo correlation may be in part attributed to poor CNS distribution. In this thesis project, we investigated the CNS distribution of three potent HDACIs, panobinostat, vorinostat, and quisinostat, following systemic administration. We characterized the systemic pharmacokinetics and CNS distributional kinetics of these compounds in wild-type and transgenic mice lacking p-glycoprotein (P-gp) and/or breast cancer resistance protein (Bcrp), two major efflux transporters expressed at the BBB. The in vitro stability studies show that all three hydroxamic acid-based HDACIs are enzymatically metabolized in mouse plasma, highlighting the need for careful sample handling to have accurate measurements of in vivo drug concentrations. In vivo experiments in the different mouse genotypes show that the CNS distribution of panobinostat and quisinostat is moderately limited by P-gp, but not Bcrp. Although the CNS penetration of vorinostat was not restricted by P-gp and Bcrp, its small unbound CNS tissue-to-plasma partition coefficients suggest that other efflux transporters could be involved. In addition, our results show that a tolerable dosing regimen of panobinostat would not result in adequate CNS exposure of unbound panobinostat in patients. In summary, our data show that the lack of adequate exposure of the active moieties can be a major reason for the lack of efficacy of these HDACIs in the CNS when systemically delivered. This result indicates that alternative approaches to improve delivery (e.g., convection-enhanced delivery or focused ultrasound) should be considered.