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Effect of darunavir and atazanavir on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Hradecká, Tereza ; Vokřál, Ivan (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Student: Tereza Hradecká Department of Pharmacology & Toxicology Supervisor: PharmDr. Vokřál Ivan, Ph.D. Oral administration of drugs is currently the most common and most convenient method of drug administration. Most drugs administered in this way are subsequently absorbed in the intestine and enter the systemic circulation. The absorption of drugs in the intestine can be influenced by a number of factors. Factors influencing drug absorption include, for example, efflux transporters or biotransformation enzymes. Currently, the most studied intestinal transporter is P-glycoprotein (P-gg), which is able to transport various substances back into the lumen of the intestine. Another factor affecting the absorption of drugs is intestinal metabolism, which in the first phase often takes place through enzymes from the cytochrome P450 family, while most drugs are metabolized through CYP3A4, which is also widely represented in the intestine. The activity of efflux transporters and biotransformation enzymes can be reduced (inhibition) or, conversely, increased (induction) by some drugs. This can subsequently lead to a whole range of drug interactions. The possible pharmacokinetic consequences of enzyme or transporter induction depend on the specific...
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Effect of dexamethasone on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Podhorná, Pavla ; Vokřál, Ivan (advisor) ; Ambrož, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Pavla Podhorná Supervisor: PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Effect of dexamethasone on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices Dexamethasone is a corticosteroid that has anti-inflammatory, immunosuppressive, and anti-allergic effects. The mechanism of dexamethasone action involves its ability to bind to intracellular glucocorticoid receptors, which are present in many types of cells, including intestinal mucosal cells. Upon binding to these receptors, it translocates to the nucleus of the cells and affects gene expression. This mechanism also affects the expression of genes important for the metabolism and transport of xenobiotics in the intestinal mucosa. The most important such genes include ABCB1, an important intestinal transporter, and CYP3A4, a significant biotransformationenzyme.Their localizationinthe wall of the small intestine can significantlyaffect the absorptionof orallyadministereddrugs.Studyingdrug interactions with this transporter and biotransformation enzyme is important for safe and effective pharmacotherapy. To determine whether dexamethasone affects the expression of these genes in the intestinal barrier,we used the method of...
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Effect of darunavir and atazanavir on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Hradecká, Tereza ; Vokřál, Ivan (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Student: Tereza Hradecká Department of Pharmacology & Toxicology Supervisor: PharmDr. Vokřál Ivan, Ph.D. Oral administration of drugs is currently the most common and most convenient method of drug administration. Most drugs administered in this way are subsequently absorbed in the intestine and enter the systemic circulation. The absorption of drugs in the intestine can be influenced by a number of factors. Factors influencing drug absorption include, for example, efflux transporters or biotransformation enzymes. Currently, the most studied intestinal transporter is P-glycoprotein (P-gg), which is able to transport various substances back into the lumen of the intestine. Another factor affecting the absorption of drugs is intestinal metabolism, which in the first phase often takes place through enzymes from the cytochrome P450 family, while most drugs are metabolized through CYP3A4, which is also widely represented in the intestine. The activity of efflux transporters and biotransformation enzymes can be reduced (inhibition) or, conversely, increased (induction) by some drugs. This can subsequently lead to a whole range of drug interactions. The possible pharmacokinetic consequences of enzyme or transporter induction depend on the specific...
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Effect of vitamin D on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Mazurová, Tereza ; Vokřál, Ivan (advisor) ; Matoušková, Petra (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Tereza Mazurová Supervisor: PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Effect of vitamin D on the expression of ABCB1 and CYP3A4 in human intestinal slices When drugs are administered orally, their absorption is significantly affected by the intestinal barrier. This barrier expresses a variety of efflux and uptake transporters, as well as first and second-phase biotransformation enzymes. The most important efflux transporter in the intestinal barrier is P-glycoprotein, which has a broad substrate specificity. Among the first-phase biotransformation enzymes, cytochrome P450 3A4 is the most important. Their function is to protect the human body from the toxic effects of xenobiotics, including drugs. Many clinically important drugs act as substrates, inhibitors or inducers in relation to these proteins, which may result in an increased risk of drug interactions. A plethora of dietary supplements or medicines containing vitamin D can be found in the pharmacy. It is used for the proper development of bones and teeth, for the proper function of the immune system or for the treatment of osteomalacia, rickets or osteoporosis. Limited information is available on its effects on P-gp and...
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Clinical classification of sequence variants in non-coding regulatory regions in breast cancer susceptibility genes.
Bubáková, Eliška ; Ševčík, Jan (advisor) ; Vodička, Pavel (referee)
Inactivation of tumor supressor gene BRCA1 causes a life-long risk of breast carcinoma development. Genetic screenings of indicated individuals from high-risk families help to identify large number of sequence variants in known predisposing genes. Majority of discovered variants doesn't have clinical significance yet which causes a big problem for diagnostics. Some of these variants are found within regulatory non-coding regions of gene. A part of the clinical classification of variants is their functional characterization. The goal of this thesis was to create a model system for functional characterization of variants in non-coding regions and to verify its function. Model system was based on targeted gene manipulation by co-transfecting CRISPR-Cas9 construct and donor construct that contained a portion of BRCA1 gene sequence with analyzed modifications, into U2 OS cells. The cells have stably integrated DR-GFP system which allows the activity of homologous recombination (HR) to be determined. Monoallelic modifications were induced into U2 OS cells. These modifications were in a Kozak sequence region of BRCA1 gene. Expression level of BRCA1 mRNA was determined by qRT-PCR, which showed the same levels of mRNA in all cells with analyzed alterations. Next, expression level of BRCA1 protein was...
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