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1
Bai, Shuang. "Effect of immunosuppressive agents on drug metabolism in rats." Thesis, Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3008270.
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Britt, Adrian John. "Cocaine metabolism in Pseudomonas maltophilia MB11L." Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386328.
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3
王漪雯 and Belinda Wong. "Haloperidol metabolism in man and animals." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1993. http://hub.hku.hk/bib/B3121194X.
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Wong, Belinda. "Haloperidol metabolism in man and animals /." [Hong Kong] : University of Hong Kong, 1993. http://sunzi.lib.hku.hk/hkuto/record.jsp?B13671546.
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5
Daneshmend, T. K. "Observations on presystemic metabolism of drugs in man." Thesis, University of Bristol, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.482894.
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6
Priston, Melanie Jane. "Studies on the pharmacokinetics and metabolism of mitozantrone." Thesis, University of Exeter, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303766.
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7
Pereira, Maria J. "Effects of immunosuppressive drugs on human adipose tissue metabolism." Doctoral thesis, University of Gothenburg, 2012. http://hdl.handle.net/10400.1/4916.
Texte intégralRésumé :
Tese de doutoramento, Philosophy (Medicine), Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska Academy, 2012<br>The immunosuppressive agents (IAs) rapamycin, cyclosporin A and tacrolimus, as well as glucocorticoids are used to prevent rejection of transplanted organs and to treat autoimmune disorders. Despite their desired action on the immune system, these agents have serious longterm metabolic side-effects, including dyslipidemia and new onset diabetes mellitus after transplantation.
The overall aim is to study the effects of IAs on human adipose tissue glucose and lipid
metabolism, and to increase our understanding of the molecular mechanisms underlying the development of insulin resistance during immunosuppressive therapy.
In Paper I and II, it was shown that rapamycin and the calcineurin inhibitors, cyclosporin A and tacrolimus, at therapeutic concentrations, had a concentration-dependent inhibitory effect
on basal and insulin-stimulated glucose uptake in human subcutaneous and omental
adipocytes. Rapamycin inhibited mammalian target of rapamycin complex (mTORC) 1 and 2
assembly and phosphorylation of protein kinase B (PKB) at Ser473 and of the PKB substrate AS160, and this leads to impaired insulin signalling (Paper I). On the other hand, cyclosporin A and tacrolimus had no effects on expression or phosphorylation of insulin signalling proteins (insulin receptor substrate 1 and 2, PKB, AS160), as well as the glucose transport proteins, GLUT4 and GLUT1 (Paper II). Instead, removal of GLUT4 from the cell surfasse was observed, probably mediated through increased endocytosis, as shown in L6 musclederived cells. These studies suggest a different mechanism for cyclosporin A and tacrolimus,
in comparison to rapamycin, with respect to impairment of glucose uptake in adipocytes.
In Paper III, all three IAs increased isoproterenol-stimulated lipolysis and enhanced phosphorylation of one of the main lipases involved in lipolysis, hormone-sensitive lipase.
The agents also inhibited lipid storage, and tacrolimus and rapamycin down-regulated gene
expression of lipogenic genes in adipose tissue. All three IAs increased interleukin-6 (IL-6), but not tumor necrosis factor α (TNF-α ) or adiponectin, gene expression and secretion.
In Paper IV, we proposed that FKBP5 is a novel gene regulated by dexamethasone, a
synthetic glucocorticoid, in both subcutaneous and omental adipose tissue. FKBP5 expression in subcutaneous adipose tissue is correlated with clinical and biochemical markers of insulin resistance and adiposity. In addition, the FKBP5 gene product was more abundant in omental than in subcutaneous adipose tissue.
In conclusion, adverse effects of immunosuppressive drugs on human adipose tissue glucose and lipid metabolism can contribute to the development of insulin resistance, type 2 diabetes and dyslipidemia in patients on immunosuppressive therapy. The cellular mechanisms that are described in this thesis should be further explored in order to mitigate the metabolic perturbations caused by current immunosuppressive therapies. The findings in this thesis could potentially also provide novel pharmacological mechanisms for type 2 diabetes as well as other forms of diabetes.
8
Godwin, Bryan. "Discrete sliding mode control of drug infusions." Thesis, Georgia Institute of Technology, 1991. http://hdl.handle.net/1853/16806.
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9
Benchaoui, Hafid Abdelaali. "Factors affecting the pharmacokinetics, metabolism and efficacy of anthelmintic drugs." Thesis, University of Glasgow, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284569.
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10
Ngulube, Thabale Jack. "The interaction of anti-malarial drugs and steroid hormone metabolism." Thesis, University of Leeds, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.329825.
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11
Frean, Stephen Philip. "Effects of anti-arthritic drugs on equine articular tissue metabolism." Thesis, Royal Veterinary College (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263731.
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12
Elayadi, Anissa N. "Metabolism and mechanism of action of acylfulvenes, novel antitumor drugs /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1999. http://wwwlib.umi.com/cr/ucsd/fullcit?p9952666.
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Gill, Helen J. "Relationship between the metabolism and toxicity of sulphones and sulphonamides." Thesis, University of Liverpool, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366003.
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14
Coller, Janet K. "The Influence of the CYP2C19 and CYP2D6 genetic polymorphisms on oxidative drug metabolism." Title page, contents and abstract only, 1999. http://web4.library.adelaide.edu.au/theses/09PH/09phc6968.pdf.
Texte intégralRésumé :
Amendements: leaves 252-254. Copies of author's previously published articles inserted. Bibliography: leaves 226-251. The CYP2C19 and CYP2D6 genetic polymorphisms control the oxidative metabolism of many different drug classes. Populations are separated into groups of extensive metabolisers (EM), poor metabolisers (PM), and in the case of CYP2D6, ultra-rapid metabolisers (UM). In vitro studies using human liver microsomes were conducted to examine the kinetics of the oxidative metabolism of flunitrazepam, and which CYP450 enzymes mediate the oxidative metabolism of flunitrazepam, (S)-mephenytoin and proguanil.
15
Xu, Hongmei. "Understanding variability in response to gliclazide." Thesis, The University of Sydney, 2009. https://hdl.handle.net/2123/28969.
Texte intégralRésumé :
Type 2 diabetes has become one of the most common human diseases. The safety and
efficacy of antidiabetic medicines is an important part of diabetes management in the
community. This thesis investigates a number of factors that may potentially cause
variability in response to the antidiabetic drug gliclazide. This information will help to
improve the use of these medicines in diabetic patients.
Patients have free access to, and commonly take, complementary medicines for a
variety of reasons. Many take these in conjunction with conventional drugs without
clear evidence of safety or risk of herb—drug interactions. St John’s wort is one of the
most widely used herbal medicines in Western societies. The aim of the first clinical
study in this thesis was to investigate potential pharmacokinetic (PK) and
pharmacodynamic (PD) interactions between St John’s wort and gliclazide in healthy
subjects with different cytochrome P450 2C9 (CYP2C9) and CYP2C19 genotypes.
16
Wong, Ka Yeung Mark. "Drug clearance mechanisms and chemotherapy response." Thesis, The University of Sydney, 2007. https://hdl.handle.net/2123/28094.
Texte intégralRésumé :
Cytotoxic chemotherapeutic agents have a major role in the treatment of cancers. However, many cytotoxic agents have a narrow therapeutic window with best treatment response achieved only within a small range of drug concentrations.
17
Schneider, Kevin. "Covalent Protein Adduction by Drugs of Abuse." FIU Digital Commons, 2013. http://digitalcommons.fiu.edu/etd/816.
Texte intégralRésumé :
Recreational abuse of the drugs cocaine, methamphetamine, and morphine continues to be prevalent in the United States of America and around the world. While numerous methods of detection exist for each drug, they are generally limited by the lifetime of the parent drug and its metabolites in the body. However, the covalent modification of endogenous proteins by these drugs of abuse may act as biomarkers of exposure and allow for extension of detection windows for these drugs beyond the lifetime of parent molecules or metabolites in the free fraction. Additionally, existence of covalently bound molecules arising from drug ingestion can offer insight into downstream toxicities associated with each of these drugs.
This research investigated the metabolism of cocaine, methamphetamine, and morphine in common in vitro assay systems, specifically focusing on the generation of reactive intermediates and metabolites that have the potential to form covalent protein adducts. Results demonstrated the formation of covalent adduction products between biological cysteine thiols and reactive moieties on cocaine and morphine metabolites. Rigorous mass spectrometric analysis in conjunction with in vitro metabolic activation, pharmacogenetic reaction phenotyping, and computational modeling were utilized to characterize structures and mechanisms of formation for each resultant thiol adduction product. For cocaine, data collected demonstrated the formation of adduction products from a reactive arene epoxide intermediate, designating a novel metabolic pathway for cocaine. In the case of morphine, data expanded on known adduct-forming pathways using sensitive and selective analysis techniques, following the known reactive metabolite, morphinone, and a proposed novel metabolite, morphine quinone methide. Data collected in this study describe novel metabolic events for multiple important drugs of abuse, culminating in detection methods and mechanistic descriptors useful to both medical and forensic investigators when examining the toxicology associated with cocaine, methamphetamine, and morphine.
18
Tory, Rita. "The study of the effect of immunosuppressive drugs on lipid metabolism." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/7593.
Texte intégralRésumé :
Introduction:
Lipid abnormalities including increased total cholesterol, triglycerides, and lowdensity
lipoprotein-cholesterol have been frequently reported in renal transplantation
and could be involved in the high frequency of cardiovascular disease in this
population. Immunosuppressive therapy appears to be a main factor that influences the
post-transplant lipid profile. Cyclosporine A (CsA), rapamycin (RAPA), tacrolimus
(TAC) and mycophenolate mofetil (MMF) are commonly used immunosuppressant in
solid organ transplant patients. Several of these immunosuppressive agents including
CsA, RAPA and TAC appear to have a significant effect on patient lipid level.
Although RAPA does not seem to cause nephrotoxicity as commonly seen in patients
treated with CsA or TAC, it seems to be associated with an incremental increase in
triglyceride level. However, the immunosuppressive-induced hyperlipidemia has not
been sufficiently described.
Purpose:
Our aim was to determine the effects of these drugs in vitro on key regulatory
enzymes of lipid metabolism; Cholesteryl Ester Transfer Protein (CETP), hepatic lipase
(HL) and lipoprotein lipase (LPL) activity within human plasma, as well as the in vivo
effects of TAC on these enzymes in renal transplant patients. In addition, we also
investigated the effects of RAPA and TAC on cholesterol efflux from human THP-l
macrophages.
Methods:
The effects of CsA, TAC, RAPA and MMF on CETP, HL and LPL activity
were first determined in vitro in human normolipidemic plasma and post-heparin
normal human plasma, respectively. We further investigated the in vivo effects of TAC
on these enzymes activities in renal transplant patients for one month following
transplantation. The cholesterol efflux study was conducted independently to assess the
effects of RAPA and TAC on ApoA-I- and HDL-mediated cholesterol efflux from
human THP-l macrophages, as well as adenosine-triphosphate binding cassette
(ABC)Al and ABCG1 protein expressions in these cells.
Results:
Our in vitro CETP study showed that CsA and RAPA induced CETP activity in
human normolipidemic plasma in a dose-dependant manner. Although, none of these
drugs, CsA, TAC, RAPA and MMF affected in vitro HL activity, these drugs
suppressed the LPL activity in the post-heparin plasma. Unlike TAC, RAPA was
shown to decrease apoAl-mediated cholesterol efflux and ABCA1 protein expression in
human THP-l macrophages. In agreement with our in vitro result, our clinical study
demonstrated that TAC significantly increased triglyceride levels and reduced the LPL
activity in the renal transplant patients, regardless of the patients were on statin or not.
Conclusions:
These findings suggest that the increase in CETP activity, suppression in LPL
activity and inhibition in the cholesterol efflux following either CsA, RAPA or TAC
treatments observed in the present study may be associated with hypercholesterolemia
and hypertriglyceridemia seen in patients administered these drugs.
19
Coulthard, Sally Anne. "The role of thiopurine methyltransferase in the metabolism of cytotoxic drugs." Thesis, University of Newcastle Upon Tyne, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323653.
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Johnson, Trevor Nigel. "Developmental and pathological changes in intestinal cytochrome P450 3A." Thesis, University of Sheffield, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.482841.
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21
Desai, Jigarkumar. "Pyridoxal Kinase: Its Role in Vitamin B6 Metabolism." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/2254.
Texte intégralRésumé :
Pyridoxal kinase (PL kinase) and pyridoxine 5’-phosphate oxidase (PNP oxidase) are the two vitamin B6 salvage enzymes involved in metabolism of the primary inactive vitamin B6 (pyridoxal, pyridoxine and pyridoxamine) into the active cofactor form, pyridoxal 5’-phosphate (PLP). PLP, arguably the most important vitamin, is required by numerous vitamin B6 (PLP-dependent) enzymes as a co-factor. These enzymes serve vital roles in the metabolism of glucose, lipids, amino acids, heme, DNA/RNA and many neurotransmitters. High levels of vitamin B6 are linked to neurotoxicity, due to the non-specific interactions of PLP with non-B6 proteins. This problem is controlled, in part, by maintaining a low in vivo concentration of free PLP (~1 μM); raising the intriguing question of how the cell regulates, as well as, supplies sufficient PLP to meet the requirements of B6 enzymes. Similar to PLP excess, PLP deficiency, due to mutations in PL kinase and PNP oxidase or drug-induced inhibition of their activity, has been implicated in many pathological conditions. The objective of this study is to elucidate the mechanisms underlying PLP regulation by PL kinase, and its subsequent transfer to dozens of PLP-dependent enzymes. A second objective is to gain valuable information into whether a missense mutation (S261F) in PL kinase could affect the enzyme activity and/or structure. A third objective is to understand how vitamin B6 metabolism by PL kinase is disrupted by the neurotoxic compound, ginkgotoxin. The mutant (hPL kinase S261F) was obtained using site-directed mutagenesis. It was then expressed, purified and analyzed by circular dichroism, fluorescence spectroscopy, enzyme kinetics and native-PAGE. Our results showed no considerable differences between wild-type enzyme and the mutant, suggesting the mutation to be non-pathogenic. PLP was found to inhibit PL kinase by binding to the substrate PL site in the presence of substrate MgATP to form an abortive ternary complex (PL kinase-PLP-MgATP). The physiological significance of this ternary complex was also analyzed and it was found to be a source of PLP transfer to apo B6 enzymes. Enzyme kinetics, affinity chromatography and fluorescence polarization techniques were used to test our hypothesis that the reactive PLP is transferred from PL kinase to apo-B6 enzymes via channeling. Channeling should provide an efficient and protected way for PLP transfer from the kinase or oxidase to apo-B6 enzymes. Our results provide a strong support to the channeling mechanism. Ginkgotoxin was found to be a competitive inhibitor of PL kinase with a Ki of 18 μM. X-ray crystallographic analysis of its binding mode to PL kinase confirmed its binding to the substrate PL site of the enzyme. A unique hydrophobic interaction between its lipophilic side chain 4’-OCH3 and nearby Tyr127 and Val231, in addition to the conserved PL binding interactions, was found to be responsible for its higher affinity to the enzyme.
22
SHROFF, PURVI B. "AN ASSESSMENT OF THE POTENTIAL INFLUENCE OF BEXAROTENE, A NOVEL RETINOID X RECEPTOR AGONIST, ON THE HEPATIC METABOLISM OF BEXAROTENE." University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1123813553.
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Chipiso, Kudzanai. "Biomimetic Tools in Oxidative Metabolism: Characterization of Reactive Metabolites from Antithyroid Drugs." PDXScholar, 2016. http://pdxscholar.library.pdx.edu/open_access_etds/3083.
Texte intégralRésumé :
Toxicities of sulfur-based drugs have been attributed to formation of highly reactive sulfur oxo-acids and depletion of glutathione by the formation of reactive metabolites. Metabolic activation of these sulfur centers to conceivably toxic reactive metabolites (RMs) that can covalently modify proteins is considered the initial step in drug-induced toxicity. Despite considerable effort and research, detection and characterization of these RMs during drug development and therapy remains a challenge. Methimazole (MMI) and 6-propyl-2-thiouracil (PTU) are two commonly used antithyroid, sulfur-based drugs. Though effective, these drugs are associated with idiosyncratic toxicity. PTU has acquired a black box warning and physicians are calling for its withdrawal. RMs resulting from bioactivation of these drugs have been implicated in the aforementioned adverse reactions. Unfortunately, isolating and detecting RMs using traditional analytical techniques has not been successful due to their high reactivity and short life span, typically less than a minute.
Current approaches in drug metabolism studies use microsomal incubations to generate RMs, which are then trapped using nucleophiles. Antithyroid drugs, however, are known to deactivate enzymes involved in their oxidation. Moreover, due to the complex nature of biological matrices and low abundance of possible toxic conjugates, this technique results in poor selectivity and sensitivity. This study developed and optimized an analytical method based on coupling electrochemical redox reactions and mass spectrometry to generate, detect and identify RMs from antithyroid drugs. The metabolites were also compared to those that were generated using chemical oxidants and biological microsomes. Mimicry of enzymatic oxidation of the antithyroid drugs was carried out by electrochemically oxidizing them using a coulometric cell coupled on-line to electrospray ionization mass spectrometry (EC/ESI-MS). Oxidation of MMI and subsequent trapping with nucleophile resulted in formation of adducts with N-acetylcysteine, revealing reactive metabolites. The most-postulated metabolite, sulfenic acid, had never been isolated or detected until now, using electrochemistry on-line with electrospray ionization. The results showed that bioactivation of MMI proceeds predominantly through the S-oxide and not through formation of thiyl radicals. These same trapping experiments were also conducted with PTU, but no conjugates were detected. The lack of conjugates from PTU does not preclude formation of RMs, but asserts radical pathway might be dominant in EC oxidation. A double mixing stopped flow was used to investigate the kinetics and mechanism of reaction of the MMI and the biologically relevant hypochlorous acid (HOCl), a product of oxidation of chloride (Cl-) ions by myeloperoxidase. The products from the chemical oxidations were compared to the electrochemically generated metabolites, some differences were apparent. Human liver microsomes (HLM) were also used, to investigate oxidation of PTU. Oxidation of PTU, resulted in the supposedly toxic S-oxide, but this has never been isolated, save for speculation. A comparison of metabolites that were found with HLM to those generated electrochemically showed some degree of similarity. These results show that in vitro techniques such as chemical oxidations and electrochemistry coupled to mass spectrometry can be used to mimic oxidative metabolism and subsequent high throughput screening of reactive metabolites.
24
Cupid, Belinda Clare. "Computational chemistry and NMR spectroscopic studies on the metabolism of model drugs." Thesis, Birkbeck (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309287.
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Gokbulut, Cengiz. "Plasma disposition, faecal excretion, metabolism and chirality of anthelmintic drugs in horses." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323707.
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Li, Nan, and 李楠. "The influence of partial hepatectomy on desmethyldiazepam formation and elimination after diazepam infusion in Chinese." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B31245687.
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Richards, R. "The metabolism and kinetics of fenfluramine, its optical isomers and a structural analogue, benfluorex." Thesis, University of Surrey, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.371816.
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Murray, Margaret. "Development of a gene therapy approach to enhance the metabolism of bioreductive drugs." Thesis, University of Ulster, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311528.
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Goold, Richard David. "Influence of endogenous female sex-steroids on mutagen metabolism." Thesis, Rhodes University, 1985. http://hdl.handle.net/10962/d1004919.
Texte intégralRésumé :
Cytochrome P-450, the terminal oxidase of the metabolic mono-oxygenase system, is thought to exist in multiple forms, which have differing substrate specificities, and are variably inducible by different enzyme inducers. Many mutagens, themselves unreactive, require metabolic activation by one or more of these cytochrome P-450-dependent microsomal enzymes for mutagenic activity. Such mutagens may be detected in the Salmonella mutagenicity test only by the incorporation of an hepatic microsomal (59) fraction into the assay (as a first approximation to in vivo metabolism). Induction of the microsomal enzymes by different agents enhances the metabolic activation of mutagens; in fact, many mutagens are only detected when the 59 fraction has been induced by appropriate agents. Inducers of the phenobarbital-type are known to enhance microsomal steroid hydroxylation when administered at supraphysiological levels, inducers of several mono-oxygenase activities. In turn, the steroids, have been reported to be The inductive effects of the female sex-steroids and the combined effects of steroid and phenobarbital (PB) pretreatment on the metabolic activation of four mutagens have been investigated using the Salmonella assay. Female Sprague-Dawley rats were pret reated with 17a-oestradiol (E2) or progesterone (PRG) , at a level of either 1 mg/kg or 20 mg / kg daily for 14 days. A duplicate set of similarly pretreated groups were also induced with PB. Hepatic microsomal fractions were prepared from each group and incubated with each of the te st mutagens in the presence of a tester strain known to detect each particular type of mutagen. Induction of the hepatic metabolizing system by PB increased the activation of the mutagens significantly (as reflected by an increased number of revertant prototrophic S .typhimurium colonies). The administration of PRG also caused significant, and dose-dependent, induction of the activation of af l atoxin B1, benzo(a)pyrene, and dimethylnitrosamine. In general, E2 exhibited no inductive effect, but it did produce an increase in the activation of aflatoxin B1 (a reaction which is known to be catalysed by a mono-oxygenase prefe rentially inducible by PB). When use was made of a microsomal fraction that was prepared from animals which were both steroidpretreated and induced by PB, mutagenic activation was of the same order of magnitude as that observed when induction was brought about by PB alone. The absence of additive effect, taken together with the observations already mentioned, indicate that steroids induce the same cytochrome isozymes that are induced by PB. The implications of sex-hormonal regulation of the metabolic activation of mutagens are briefly discussed.<br>KMBT_363<br>Adobe Acrobat 9.53 Paper Capture Plug-in
30
Madani, Soraya. "The role of CYP2D6 and CYP3A4 in first-pass intestinal drug metabolism /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/7942.
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Bowers, Gary David. "Applications of mass spectrometric techniques to the monitoring of drugs and their metabolic conjugates in biological media." Thesis, King's College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363143.
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Yang, Jun. "Approaches to prostate cancer imaging and therapy the use of pharmacokinetics, metabolism and biodistribution to identify new drugs /." Columbus, Ohio : Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1133362520.
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Rousu, T. (Timo). "Liquid chromatography–mass spectrometry in drug metabolism studies." Doctoral thesis, Oulun yliopisto, 2012. http://urn.fi/urn:isbn:9789514298172.
Texte intégralRésumé :
Abstract Drug metabolite profiling and identification studies are nowadays regularly conducted with liquid chromatography (LC) coupled with mass spectrometry (MS) as an analytical tool. The speed, selectivity and sensitivity of modern LC–MS instruments have been significantly increased in recent years. Especially the use of ultra-high-performance LC (UHPLC) in combination with a modern high-resolution MS instrument offers high full scan detection sensitivity, mass accuracy and the detection of both expected and unexpected metabolites in a single LC–MS run. The present study showed that no single LC–MS conditions were suitable for the analysis of a large group of structurally diverse compounds. The testing of optimum conditions for each individual compound led to more high-quality data when chromatographic retention behavior and mass spectrometric ionization efficiency for in vitro metabolite profiling were considered. The developed LC–MS methods were applicable for measuring both the disappearance of the parent compound and the formation of metabolites. Tentative metabolite identification was based on the measured accurate mass time-of-flight (TOF) MS data. In the second part, a rapid and sensitive assay was designed and built for the trapping, screening and characterization of reactive metabolites in vitro. In total, 78 trapped reactive metabolite conjugates were detected and identified based on accurate mass data using 12 structurally different test compounds. The majority of the detected conjugates were reported for the first time. Amine-containing compounds, that formed methylated and cyanide-trapped products after CYP-mediated reaction steps in human liver microsomal (HLM) incubations, were studied further. The observed methylated cyano conjugates were shown to be experimental artifacts, i.e., metabonates. The study also describes the use of traditional high-performance LC (HPLC) and the more modern UHPLC coupled to time-of-flight, triple quadrupole and hybrid linear ion trap mass spectrometers in drug metabolism studies, and reviews on how to choose the most suitable LC–MS system for metabolite profiling purposes in drug discovery and early drug development<br>Tiivistelmä Nestekromatografia (LC) yhdistettynä massaspektrometriaan (MS) on nykyaikana yleisesti käytetty analyysimenetelmä lääkeaineiden aineenvaihduntatuotteiden (metaboliittien) havaitsemisessa ja tunnistamisessa. Modernien LC–MS -laitteiden nopeus, selektiivisyys ja herkkyys ovat merkittävästi parantuneet viime vuosina. Käytettäessä ultrakorkean suorituskyvyn nestekromatografia (UHPLC) yhdessä nykyaikaisen korkean massaresoluution MS-laitteen kanssa on mahdollista havaita kaikki sekä odotetut että odottamattomat metaboliitit yhdellä kertaa. Tutkimalla suurta joukkoa rakenteellisesti erilaisia yhdisteitä voitiin todeta, että yksittäiselle yhdisteelle optimoidut mittausolosuhteet johtivat korkealaatuisempaan dataan kuin yleiset ei-optimoidut olosuhteet, kun arvioitiin sekä kromatografista piikin profiilia ja pidättymistä että ionisaatiotehokkuutta. Yksikään yksittäinen analyysiolosuhde ei myöskään soveltunut kaikille yhdisteille. Tutkimuksessa kehitetyillä LC–MS -analyysimenetelmillä tutkittiin sekä kanta-aineen häviämistä että metaboliatuotteiden muodostumista in vitro -menetelmillä. Alustava metaboliatuotteiden tunnistus perustui tarkan massan mittaukseen lentoaikamassaspektrometrillä (TOFMS). Tutkimustyön seuraavassa vaiheessa kehitettiin nopea ja herkkä analyysimenetelmä reaktiivisten metaboliittien pyydystämiseen, havaitsemiseen ja tunnistamiseen ihmisen maksamikrosomivalmisteista in vitro -menetelmin. 12 testiyhdisteelle havaittiin kaikkiaan 78 erilaista reaktiivisen metaboliitin konjugaatiotuotetta, jotka tunnistettiin tarkan massan perusteella. Suurin osa tunnistetuista konjugaatiotuotteista raportoitiin ensimmäistä kertaa. Amiineja sisältäville testiyhdisteille havaittiin muodostuvan sytokromi P450 (CYP) entsyymien katalysoimien reaktioiden välityksellä metyloituneita ja syanidianionilla konjugoituneita metaboliatuotteita. Tarkempien tutkimusten jälkeen näiden todettiin olevan koejärjestelyistä johtuvia artefaktoja, toisin sanoen metabonaatteja, eivätkä todellisia reaktiivisten metaboliittien konjugaatiotuotteita. Tässä tutkimuksessa arvioitiin myös perinteiseen korkean suorituskyvyn nestekromatografiin (HPLC) sekä uudempaan UHPLC-laitteistoon kytkettyjen lentoaika-, kolmoiskvadrupoli- ja hybridimallisten ioniloukkumassaspektrometrien soveltuvuutta aikaisen lääkekehitysvaiheen metaboliatutkimuksiin
34
Chang, Robert Chao Sun Wei. "Biofabrication of three-dimensional liver cell-embedded tissue constructs for in vitro drug metabolism models /." Philadelphia, Pa. : Drexel University, 2009. http://hdl.handle.net/1860/3069.
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El-Sankary, Wafaa Mahmoud. "Regulation of the human CYP3A4 gene." Thesis, University of Surrey, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326904.
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Angell, Johanna Elizabeth. "Use of Bioluminescent Bacterial Biosensors to Study the Intracellular Metabolism of Anti-Cancer Drugs." Thesis, University of the West of England, Bristol, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.524687.
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Scott, A. O. "The role of the gastrointestinal tract in the metabolism of labetalol and other drugs." Thesis, University of Surrey, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.354231.
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Verenich, Svetlana. "ROLE OF OXIDATIVE REACTIVE SPECIES AND ANTIOXIDANTS IN METABOLISM AND TRANSPORT OF THERAPEUTIC DRUGS." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/96.
Texte intégralRésumé :
Oxidative stress (OS) is a frequent complication of various disease conditions such as Alzheimer’s and Parkinson’s disease, atherosclerosis, preeclampsia, rheumatoid arthritis, diabetes including gestational diabetes, etc. OS is defined as an imbalance between the production of reactive species and the ability of an organism to detoxify the reactive intermediates and repair the damage. As a result of OS, the excess of reactive species such as oxygen superoxide (O2-), hydroxyl radical (OH), peroxynitrite (ONOO−), 4-hydroxynonenal (4HNE), etc., have a tendency to react with nearby proteins/nucleic acids/lipids changing their functionality or inactivating them completely. The organism has many ways to protect itself from the harmful effects of oxidants. One strategy employs antioxidants introduced to the body with food. The purpose of this thesis was to investigate the effect of reactive species on the active transport mediated by ABC efflux transporters as well as exploring the possibility of using antioxidants not as interceptors of reactive species but rather as inhibitors of metabolic enzymes and transporters. The BCRP/ABCG2 efflux transporter was selected for the investigation of the effect of reactive anion, ONOO−, generated during OS and the product of OS, 4HNE, formed after a series of chain reactions involving ROS. Experiments conducted with Sf9 membrane vesicles overexpressing BCRP/ABCG2 revealed that both species are capable of inactivating this ABC transporter with IC50 being 31 ± 2.7 μM and 92 ± 1.4 μM for ONOO− and 4HNE, respectively. In presence of 4HNE, Vmax decreased 4-fold and Km remained unchanged, suggesting a noncompetitive inhibition mechanism. However, with addition of 4HNE, positive cooperativity was also observed. With ONOO−, the situation was different: both Vmax and Km changed consistent with mixed type inhibition. Overall, OS-mediated BCRP/ABCG2 inactivation occurred at biologically relevant concentrations of the reactive species. Antioxidants are substances that are known to reduce the amount of ROS/RNS accumulated during OS, but this research considered the use of antioxidants not only as interceptors of ROS/RNS but rather as inhibitors of metabolic enzymes. The effect of the dietary antioxidant, quercetin (Qc), on the metabolism of 2-methoxyestradiol (2Me-E2), a promising potential anticancer agent was investigated. Qc possesses five hydroxyl groups, several of which are targets for UDP-glucuronosyltransferases (UGTs). Thus, the simultaneous presence of Qc and 2Me-E2 could result in decreased glucuronidation of 2Me-E2. Using the LS180 intestinal human colon adenocarcinoma cell line, glucuronidation of 2Me-E2 resulted in formation of only one major glucuronide, 2-Methoxyestradiol-3-glucuronide (2Me-E2-3G). Qc effectively reduced its formation (IC50 = 7.8 ± 0.26 μM) to a minimum level. The decrease in the activity of UGTs increased the intracellular concentration of parent 2Me-E2. Additional increase in cellular concentration of 2Me-E2 was achieved when LS180 cells were pre-incubated with Qc prior the addition of 2Me-E2. Transwell experiments with MDCKII – BCRP cells revealed that BCRP/ABCG2 did not appear to transport 2Me-E2. All in all, the present study showed that OS has a negative impact on active transport mediated by ABC transporters. This, in turn, can affect drug disposition and protection of endogenous organs and tissues. Antioxidants are one of the mechanisms that can effectively reduce the negative impact caused by oxidative species. Nevertheless, this research revealed that they can also be an effective tool to reduce the excessive metabolism of therapeutic drugs. Thus, Qc was found to be a dietary antioxidant that could reduce metabolism of 2Me-E2 and increase it intracellular concentration.
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Morrison, Roxanne. "The development of an in vitro system for the production of drug metabolites using microsomal enzymes from bovine liver." Thesis, Rhodes University, 2011. http://hdl.handle.net/10962/d1007698.
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Drug metabolism is a specialised subset of xenobiotic metabolism, pertaining to the breakdown and elimination of pharmaceutical drugs. The enzymes involved in these pathways are the cytochrome P450 family of isozymes. Metabolism is an important factor in determining the pharmacological effects of drugs. The main aim of this study was to develop a system whereby the major metabolites of drugs can be produced in vitro. An in vitro system was developed and optimised using commercially prepared microsomes from rat liver and coumarin (by monitoring its conversion to 7-hydroxycoumarin) as a model. The optimum running conditions for the incubations were 50 μM coumarin, 50 μg protein/ml microsomes, 1 mM NADP⁺, 5 mM G6P and 1U/ml G6PDH incubated for 30 minutes at 38℃. The HPLC method for the detection of coumarin and 7-hydroxycoumarin was also validated with respect to linearity, reproducibility, precision, accuracy and lower limits of detection and quantification. The system developed was then tested using microsomes prepared from fresh bovine liver on these ten drugs of interest in doping control in horse racing: diazepam, nordiazepam, oxazepam, promazine, acepromazine, chlorpromazine, morphine, codeine, etoricoxib and lumiracoxib. The bovine liver microsomes were prepared using differential centrifugation and had activity on a par with the commercial preparations. This in vitro system metabolised the drugs and produced both phase I and II metabolites, similar to those observed in humans and horses in vivo. For example, the major metabolites of the benzodiazepine drug, diazepam, nordiazepam, temazepam and oxazepam as well as the glucuronidated phase II products were all found after incubations with the bovine liver microsomes. The metabolism of the drugs was also investigated in silico using the computational procedure, MetaSite. MetaSite was able to successfully predict known metabolites for most of the drugs studied. Differences were observed from the in vitro incubations and this is most likely due to MetaSite using only human cytochrome P450s for analysis.
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Potter, Michelle. "Development of models and methods to assess the efficacy of anti-cancer drugs targeted to the mitochondria." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:6a847ae9-3664-437e-ad26-c1ae3d94f7c0.
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<strong>Background:</strong> Malignant transformation of cells is typically characterised by aerobic glycolysis, resulting in supressed mitochondrial function, a state that helps resistance to apoptosis. This characteristic has been widely accepted as a hallmark of cancer and has been shown to be of critical importance in tumour development. The bioenergetic differences between normal and malignant cells are being exploited to identify potential cancer specific therapeutics. Improved in-vitro models are required to aid the identification and assessment of candidate drugs. In this project, we investigated the bioenergetic phenotypes of a panel of adult and paediatric cancer cell lines and evaluated the potential of 3D models as a platform for testing drugs that target cancer metabolism. We also investigated a novel method to assess mitochondrial function that enables the quantification of the level of oxygenation within the cell. <strong>Results:</strong> The results presented in this thesis show that not all cancers display this aerobic glycolytic phenotype. We found that while some cell lines displayed the Warburg phenotype others displayed high levels of oxidative metabolism. These bioenergetic profiles need to be considered when deciding which anti-cancer drugs to use in a chemotherapeutic regime. If a bioenergetic pattern can be identified it may one day form the basis of a screening strategy for tumours. Dichloroacetate (DCA) is a small molecule PDK inhibitor that was investigated in this study. It was found to be relatively non-toxic to cells cultured in 2D but had improved toxicity when the cells were cultured in a 3D environment. Lastly, we evaluated a new oxygen sensing nanoprobe, Mito-Xpress Intra, and the results demonstrate its potential as a non-invasive means of measuring oxygen concentrations within the cell in real time as well as highlighting some striking differences between applied ambient and measured intracellular oxygen concentrations. <strong>Conclusion:</strong> The findings suggest that not all cancers display the characteristic glycolytic phenotype. They also highlight the importance of controlling oxygen and glucose levels when evaluating metabolism and when drug testing.
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Gandhi, Amit. "VITAMIN B6 METABOLISM AND REGULATION OF PYRIDOXAL KINASE." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/2008.
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Pyridoxal 5'-phosphate (PLP) is the cofactor for over 140 vitamin B6 (PLP)-dependent enzymes that are involved in various metabolic and biosynthetic pathways. Pyridoxal kinase (PL kinase) and pyridoxine 5’-phosphate oxidase (PNP oxidase) are the two key enzymes that metabolize nutritional forms of vitamin B6, including pyridoxal (PL), pyridoxine (PN), and pyridoxamine (PM) to the active cofactor form, PLP. Disruption of the PLP metabolic pathway due to mutations in PNP oxidase or PL kinase result in PLP deficiency, which is implicated in several neurological pathologies. Several ingested compounds are also known to result in PLP deficiency with concomitant neurotoxic effects. How these mutations and compounds affect B6 metabolism is not clearly understood. On the other hand, an emerging health problem is the intake of too much vitamin B6 as high doses of the reactive PLP in the cell exhibits toxic effects, including sensory and motor neuropathies. The overall aim of this research is to understand the catalytic function of PL kinase and the regulatory pathway of PLP metabolism. Using site-directed mutagenesis (Asp235Asn, Asp235Ala), kinetic and structural studies, we have shown that Asp235 may play a catalytic role in PL kinase phosphorylation activity. We also show that human PL kinase binds its substrates, PL and MgATP synergistically, and that the enzyme requires Na+ (or K+) and Mg2+ for its activity. Using kinetic study, we show severe induced MgATP substrate inhibition of PL kinase in the presence of its product, PLP, and we postulate this to be due to the formation of a non-productive ternary complex (Enzyme•PLP•MgATP). Consistently, our crystal structure of human PL kinase (2.1 Å) co-crystallized with MgATP and PLP showed both MgATP and PLP trapped at the active site. Our hypothesis is that this abortive ternary complex might be a physiological process, and that PL kinase uses this mechanism to self-regulate its activity. Our inhibition studies show theophylline, a bronchodilator as a mixed competitive inhibitor of human PL kinase with Ki of 71 μM. Our structural study (2.1 Å) shows theophylline bound at the substrate, PL binding site of human PL kinase. We also identified several potential PL kinase inhibitors from the DrugBank Chemical Compound database. Some of these compounds, including enprofylline, theobromine, caffeine, and lamotrigine, which incidentally exhibit similar neurotoxic effects as theophylline, show significant inhibitory effect on human PL kinase. Further studies are also planned to investigate the effect of these drugs on vitamin B6 metabolism in vivo.
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Sek, Leab 1973. "An in vitro model of lipid digestion for assessing the oral bioavailability enhancement potential of lipidic formulations." Monash University, Dept. of Pharmaceutics, 2002. http://arrow.monash.edu.au/hdl/1959.1/8215.
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Karve, Sayali. "Role of pyridoxine 5'-phosphate oxidase in metabolism and transfer of pyridoxal 5'-phosphate." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/2253.
Texte intégralRésumé :
Deficiency of vitamin B6 due to mutations in key B6 metabolizing enzymes is suspected to contribute to several pathologies. Vitamin B6 in its active form, pyridoxal 5’-phosphate (PLP) is a cofactor for over 140 known B6 requiring (or PLP-dependent) enzymes, that serve vital roles in many biochemical reactions. There are three primary vitamin B6 forms, pyridoxine (PN), pyridoxamine (PM) and pyridoxal (PL) which are phosphorylated to pyridoxine 5’-phosphate (PNP), pyridoxamine 5’-phosphate (PMP) and PLP respectively. Pyridoxal kinase (PLK) and pyridoxine 5’-phosphate oxidase (PNPO) are the key enzymes involved in both salvage and de novo pathways of PLP biosynthesis. Mutations in these enzymes are one of the most important causes of PLP deficiency, apart from dietary insufficiency of vitamin B6 and drug inhibition of PLK and PNPO. One of our objectives is to understand the molecular basis of reduced catalytic activity of PNPO in case of the R95C homozygous missense natural mutant, which leads to the PLP deficiency and the debilitating disease, neonatal epilepsy encephalopathy. Using site-directed mutagenesis, circular dichroism, enzyme kinetics and fluorescence spectroscopy, we have shown that the reduced enzymatic activity exhibited by PNPO R95C mutant is due to reduced binding affinity of the oxidase cofactor, flavin mononucleotide (FMN), which is required by the enzyme for oxidizing the inactive B6 vitamers into the active PLP. High concentrations of B6 are linked to neurotoxic effects, which can be attributed to the highly reactive aldehyde group of PLP which reacts with many nucleophiles in the cell. This reactivity is most likely why the in vivo concentration of “free” PLP is about 1 μM, raising the intriguing question of how the cell supplies sufficient PLP to meet the requirements of the numerous B6 dependent enzymes. Our second objective is to determine how despite the low in vivo concentration of free PLP, enough of this co-factor is made available to activate PLP-dependent enzymes. We have used affinity pull down assays, fluorescence polarization and enzyme kinetics to show that PNPO forms specific interactions with B6 enzymes with dissociation constants less than 1 µM. We also show that transfer of PLP from PNPO possibly occurs by compartimentalization or channeling. Although, channeling is a controversial subject, it offers an efficient, exclusive, and protected means of delivery of the highly reactive PLP. High concentrations of B6 are linked to neurotoxic effects, which can be attributed to the highly reactive aldehyde group of PLP which reacts with many nucleophiles in the cell. This reactivity is most likely why the in vivo concentration of “free” PLP is about 1 ?M, raising the intriguing question of how the cell supplies sufficient PLP to meet the requirements of the numerous B6 dependent enzymes. Our second objective is to determine how despite the low in vivo concentration of free PLP, enough of this co-factor is made available to activate PLP-dependent enzymes. We have used affinity pull down assays, fluorescence polarization and enzyme kinetics to show that PNPO forms specific interactions with B6 enzymes with dissociation constants less than 1 µM. We also show that transfer of PLP from PNPO possibly occurs by compartimentalization or channeling. Although, channeling is a controversial subject, it offers an efficient, exclusive, and protected means of delivery of the highly reactive PLP.
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Kerry, David Michael Kerry. "Regulation of the rat 25-hydroxyvitamin D3 24-hydroxylase gene promoter by 1,25(OH)2D3 /." Title page, contents and summary only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phk416.pdf.
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Ventura, Ventanachs Verònica. "In vitro metabolism and drug-drug interaction potential of irosustat, a steroidal sulfatase inhibitor." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/124483.
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Irosustat is a first-generation, irreversible, steroid sulfatase inhibitor currently in development for hormone-dependent cancer therapy. Its structure is a tricyclic coumarin-based sulfamate that undergoes desulfamoylation in aqueous solution, yielding the sulfamoyl-free derivative, 667-coumarin.
The first aim of the present work was to study the in vitro metabolism of irosustat, including its metabolic profile in liver microsomes and hepatocytes, the potential species differences, and the identification of the main metabolites. And the second aim of the present work was to predict potential drug-drug interactions between irosustat and possible concomitantly administered medications through the investigation in vitro of the enzymes participating in the metabolism of irosustat and its inhibition/induction potential with the main drug-metabolizing enzymes. The interaction of aromatase inhibitors in the in vitro metabolism of irosustat was also studied.
Irosustat was extensively metabolized in vitro, showing similar metabolite profiles among rat, dog, monkey, and humans (both sexes). In liver microsomes, the dog was the species that metabolized irosustat most similarly to metabolism in humans. Marked differences were found between liver microsomes and hepatocytes, meaning that phase I and phase II enzymes contribute to irosustat metabolism. Various monohydroxylated metabolites of irosustat and of 667-coumarin were found in liver microsomes, which mostly involved hydroxylations at the C8, C10, and C12 positions in the cycloheptane ring moiety. 667-Coumarin was formed by degradation but also by non-NADPH-dependent enzymatic hydrolysis, probably catalyzed by microsomal steroid sulfatase. The main metabolites formed by hepatocytes were glucuronide and sulfate conjugates of 667-coumarin and of some of its monohydroxylated metabolites.
The major cytochrome P450 enzymes involved in the transformation of irosustat were CYP2C8, CYP2C9, CYP3A4/5, and CYP2E1. Moreover, various phase II enzymes (UDP-glucuronosyltransferases and sulfotransferases) were capable of conjugating many of the metabolites of irosustat and 667-coumarin; however, the clinically relevant isoforms could not be elucidated.
Irosustat inhibited CYP1A2 activity in human liver microsomes through the formation of its desulfamoylated degradation product and metabolite 667-coumarin. CYP1A2 inhibition by 667-coumarin was competitive, with a K(i) of 0.77 μM, a concentration exceeding by only 5-fold the maximal steady-state concentration of 667-coumarin in human plasma with the recommended dose of irosustat. In addition, 667-coumarin metabolites enhanced the inhibition of CYP1A2 activity. Additional clinical interaction studies of irosustat with CYP1A2 substrate drugs are strongly recommended. 667-Coumarin also appeared to be a competitive inhibitor of CYP2C19 (K(i) = 5.8 μM) in human liver microsomes, and this inhibition increased with assessment in human hepatocytes. Inhibition of CYP2C19 enzyme activity was not caused by repression of CYP2C19 gene expression. Therefore, additional mechanistic experiments or follow-up studies with clinical evaluation are recommended. Irosustat neither inhibited CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, or UDP-glucuronosyltransferase 1A1, 1A4, or 2B7 activities nor induced CYP1A2, CYP2C9, CYP2C19, or CYP3A4/5 at clinically relevant concentrations. Results from human liver microsomes indicated that no changes in irosustat pharmacokinetics in vivo are expected as a result of inhibition of irosustat metabolism in cases of concomitant medication administration or irosustat-aromatase inhibitor combination therapy with letrozole, anastrozole, or exemestane.<br>Irosustat és un inhibidor irreversible de la sulfatasa esteroidal, de primera generació, actualment en desenvolupament per al tractament del càncer dependent d'hormones.
Els objectius d'aquest treball van ser estudiar el metabolisme in vitro d'irosustat, incloent el seu perfil metabòlic en microsomes hepàtics i hepatòcits, les diferències entre espècies, així com la identificació dels principals metabòlits. I també predir les possibles interaccions fàrmac-fàrmac entre irosustat i possibles medicaments administrats de forma concomitant, a través de la investigació in vitro dels enzims que participen en el metabolisme de irosustat i el seu potencial d'inhibició / inducció dels principals enzims metabolitzants de fàrmacs. La interacció dels inhibidors de l'aromatasa en el metabolisme in vitro del irosustat també es va estudiar.
Irosustat és extensament metabolitzat in vitro, mostrant perfils metabòlics similars entre rates, gossos, micos i humans (ambdós sexes). En microsomes de fetge, el gos va ser l'espècie que metabolitza irosustat de forma més similar al metabolisme en humans. 667-coumarin es va formar per degradació, però també per hidròlisi enzimàtica no dependent de NADPH, probablement catalitzada per la sulfatasa esteroidal microsomal. Es van trobar grans diferències entre els perfils metabòlics de microsomes hepàtics i de hepatòcits, significant que tant enzims de fase I com de fase II contribueixen al metabolisme del irosustat. Els principals metabòlits formats pels microsomes de fetge van ser monohidroxilats del irosustat i de la 667-coumarin, mentres que en hepatòcits van ser conjugats glucurònids i sulfats de 667-coumarin i d'alguns dels seus metabòlits monohidroxilats.
Els principals enzims del citocrom P450 involucrats en la transformació del irosustat van ser CYP2C8, CYP2C9, CYP3A4/5, i CYP2E1. D'altra banda, diversos enzims de fase II (UDP-glucuronosiltransferasas i sulfotransferasas) eren capaços de conjugar molts dels metabòlits de irosustat i 667-coumarin, però, les isoformes clínicament rellevants no es van poden dilucidar.
Irosustat inhibeix les activitats dels CYP1A2 i CYP2C19 en microsomes de fetge humà a través de la formació de 667-coumarin. Es recomanen estudis clínics addicionals d'interacció entre irosustat i substrats del CYP1A2. Pel CYP2C19, aquesta inhibició va augmentar amb l'avaluació en hepatòcits humans, tot i que no va ser causada per la repressió de l'expressió del gen CYP2C19. Per tant, es recomanen experiments mecanistics addicionals o estudis de seguiment amb avaluació clínica.
Irosustat no inhibeix CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, UGT1A1, UGT1A4 ni UGT2B7. Tampoc indueix CYP1A2, CYP2C9, CYP2C19 o CYP3A4/5, a concentracions clínicament rellevants. Els resultats dels microsomes hepàtics humans van indicar que no s'espera canvis en la farmacocinètica del irosustat com a resultat de la inhibició del seu metabolisme en els casos d'administració concomitant d’inhibidors de l’aromatase: letrozole, anastrozole, o exemestane.
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Thörn, Helena Anna. "First-pass Intestinal Metabolism of Drugs : Experiences from in vitro, in vivo and simulation studies." Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-165514.
Texte intégralRésumé :
The bioavailability of a drug can be described as the fraction of an orally administered dose that reaches the systemic circulation and is often limited by first-pass metabolism in the gut and the liver. It is important to have knowledge about these processes since the systemic blood drug concentration is tightly connected to the effect of the drug. The general aim of this project was to quantitatively examine the role of the intestine in relation to the liver in first-pass metabolism of orally administered drugs. The first-pass metabolism of verapamil and raloxifene was investigated in detail with in vivo, in vitro and simulation studies, using the pig as an experimental model. The intestine contributed to the same extent as the liver to first-pass metabolism of R/S-verapamil in vivo in pigs. The S-isomer of verapamil was found in lower plasma concentrations compared to the R-isomer after oral dosing. The in vitro metabolism of verapamil in pig and human liver showed interspecies similarity and indicated equal intrinsic clearance for R- and S-verapamil. Through physiologically based pharmacokinetic modeling the stereoselectivity was explained by a combination of several processes, including enantioselective plasma protein binding, blood-to-plasma partition, and gut and liver tissue distribution. For raloxifene the intestine was the dominating organ in first-pass glucuronidation in vivo in pigs. Furthermore, the raloxifene concentration entering the intestine or the dose administered in the gut did not influence the plasma PK of raloxifene and indicated that the intestinal metabolism was not saturable with clinical relevant doses. For both verapamil and raloxifene, a time-dependent hepatic metabolism was noted with major consequences to the pharmacokinetic of the drugs. This project has pointed out the importance of intestinal metabolism in the overall first-pass extraction of drugs and indicates that intestinal metabolism should be considered and evaluated early in drug development.
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Laing, Steven. "Caenorhabditis elegans as a model for nematode metabolism of the anthelmintic drugs ivermectin and albendazole." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/1781/.
Texte intégralRésumé :
Resistance to anthelmintics used to treat parasitic nematodes of veterinary importance represents a serious welfare and economic problem for the livestock production industry. Research into the mechanisms by which parasites develop resistance is necessary to prolong the life of the available drugs and to minimise development of resistance to new classes. Metabolism of anthelmintic compounds by parasites is a possible mechanism of resistance that has received little research, despite there being precedence in the case of insecticide resistance. Due to the more advanced molecular tools available and comparative ease of manipulation; we have used the model nematode Caenorhabditis elegans to investigate the metabolism of two important anthelmintic drugs, ivermectin and albendazole. Whole genome microarrays and RT-QPCR were used to identify clusters of genes, which are significantly up-regulated upon exposure of C. elegans to anthelmintic. The transcriptomic response to albendazole is characterised by genes potentially involved in xenobiotic metabolism. These include members of the cytochrome P450 family and the UDP-glucuronosyl/ glucosyl transferase family. In contrast, the response to ivermectin appears to represent a fasting response caused by the phenotype of drug exposed nematodes. Recombinant worms carrying GFP reporter constructs of several genes of interest demonstrated their expression in the intestine, which is thought to be the main site of xenobiotic detoxification in nematodes. HPLC-MS techniques have definitively shown that C. elegans is able to metabolise albendazole to two glucose conjugates. These metabolites are compatible with the transcriptomic response to the drug and are similar to albendazole metabolites produced by the parasitic nematode Haemonchus contortus. No ivermectin metabolites were identified in the current study. The data presented confirms the ability of the nematode C. elegans to respond to and metabolise anthelmintic compounds. In addition, the study validates the use of C. elegans as a model organism for parasitic nematodes and provides a platform upon which to investigate nematode metabolism further.
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Lambert, Craig. "A study of the role of metabolism in the toxicity of mianserin and other drugs." Thesis, University of Liverpool, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314496.
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Balaños, Guzman Carlos Alberto. "The effects of the kappa agonist U-50,488 on morphine-induced place preference conditioning and Fos immunoreactivity in the preweanling and periadolescent rat." CSUSB ScholarWorks, 1995. https://scholarworks.lib.csusb.edu/etd-project/1074.
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The effects of the kappa opioid agonist U-50,488 on morphine-induced condtioned place preference (CPP), locomotor activity and Fos immunoreactivity and assessed in 10-, 17- and 35-day old rats. It was predicted that kappa agonist treatment would block the unconditioned and conditioned behaviors produced by morhine (a mu opioid receptor agonist).
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Christensen, Magnus. "Experimental design of phenotyping probe drugs with emphasis on CYP1A2 : their use in studies on genetic and environmental regulation of drug metabolism /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-522-0.
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