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Role of selected ABC and SLC transporters in transmembrane permeability of maraviroc: effect on transport in placenta
Matiašková, Zuzana ; Čečková, Martina (advisor) ; Vopršalová, Marie (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and toxikology Student: Zuzana Matiašková Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Role of selected ABC and SLC transporters in transmembrane permeability of maraviroc: effect on transport in placenta Antiretroviral drug maraviroc is an inhibitor of CCR5-trophic HIV virus and belongs to the group of entry inhibitors. Nowadays, maraviroc is administered as part of combination antiretroviral therapy (cART) primarily in adults, children over the age of two and pregnant women to reduce the risk of transmission of HIV to the fetus. The knowledge of interactions of maraviroc with drug transporters in placenta is crucial for optimizing the therapy during pregnancy, both in terms of efficacy and potential adverse effects. Maraviroc is known substrate of ABCB1 transporter, which plays a protective role to the fetus by its efflux activity in the apical membrane of trophoblast. However, the results of recent study employing dually perfused human placenta suggest involvement of other transport mechanisms in the maraviroc transplacental pharmaocokinetics, especially those operating in the opposite direction to ABCB1. The aim of this study was to evaluate in vitro studies whether, besides ABCB1,...
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Effect of CDK and FLT3 inhibitors on activity of ABC efflux transporters in vitro, relation to multidrug resistance
Poráč, Jakub ; Čečková, Martina (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Jakub Poráč Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Effect of CDK and FLT3 inhibitors on activity of ABC efflux transporters in vitro, relation to multidrug resistance P-gp and BCRP are transmembrane proteins that form part of a large family of ABC transporters. These are ATP-driven transporters, which main task is to eliminate exogenous and endogenous substances and their metabolites from cells of both, healthy and tumour tissues. This activity is often associated with the expulsion of administered therapeutics and multiple drug resistance (MDR) in tumour cells. A promising therapy of cancer represents a newer class of drugs target the tyrosine kinase (TK), and cyclin-dependent kinases (CDK), which are cell enzymes responsible for the processes of proliferation, apoptosis and differentiation. Cyclin- dependent kinase inhibitors (CDKI) are used in the treatment of breast cancer, but at the same time they form a new group of drugs with the potential for use in hematological malignancies. In the treatment of AML, a new successful approach is TK inhibitors (TKI), which target the mutated FLT3 receptor, specifically the recently approved drugs midostaurin and...
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Interactions of selected antiretroviral drugs and methylmercury with placental membrane transporters
Ťupová, Lenka ; Čečková, Martina (advisor) ; Fusek, Josef (referee) ; Kacerovský, Marian (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Lenka Ťupová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of doctoral thesis: Interactions of selected antiretroviral drugs and methylmercury with placental membrane transporters. Pregnant women are especially in developed countries exposed to high amount of various xenobiotic including environmental pollutants and drugs. Antiretroviral therapy (ART) is administered to HIV positive pregnant women for the purpose of prevention of HIV mother- to-child-transmission. Pharmacokinetics of many antiretrovirals is limited or enhanced by activity of ATP-binding cassette (ABC) or Solute carrier's transporters, of which many are expressed also in placental tissue. ART therapy usually consists of combination of 3 - 4 antiretroviral drugs, thereby leading to higher risk for development of drug-drug interactions on ABC and SLC transporters. In this study we described influence of non-nucleoside reverse transcriptase inhibitors etravirin and rilpivirin on BCRP- and MDR1-mediated transport of tenofovir disoproxil fumarate (TDF) and/or abacavir. Etravirin showed potent inhibition of BCRP transporter significantly changing transport of both, TDF and abacavir, across monolayers of MDCKII-BCRP...
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The effect of in vitro and ex vivo placental cells stimulation on expression of selected ABC and OATP transporters
Dudičová, Simona ; Čečková, Martina (advisor) ; Jirkovská, Anna (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Simona Dudičová Supervisor: Assoc. Prof. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: The effect of in vitro and ex vivo placental cells stimulation on expression of selected ABC and OATP transporters The placenta is an organ that plays a key role throughout pregnancy for proper fetal development. One of the important functions provided by the placenta is the transport of substances between the mother and the fetus. This transfer of substances enabled mainly by membrane transporters, which are located on the apical and basal membranes of the syncytiotrophoblast. During various physiological or pathological changes in the human body, their expression and amount can vary significantly. Inflammatory reactions that may occur during pregnancy are also related to these changes, and therefore we have addressed this issue and believed that this condition may alter the expression of placental transporters. The aim of this work was to investigate the changes in the expression of membrane transporters using placental cells on BeWo cell lines and placental villous explants that were stimulated by pro-inflammatory mediators. The change in the expression of individual ATP-binding cassettes,...
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Study of the effect of roscovitine and its derivatives on the expression of drugs transporters in vitro
Mlčochová, Alice ; Čečková, Martina (advisor) ; Carazo Fernández, Alejandro (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Mgr. Alice Mlčochová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of rigorous thesis: Study of the effect of roscovitine and its derivatives on the expression of drugs transporters in vitro In this study we aimed to evaluate interactions of selected inhibitors of cyclin-dependent kinases (CDKi) with efflux transporters ABCB1 (P-glycoprotein, P-gp, MDR1) and ABCG2 (breast cancer resistance protein, BCRP) in cell line LS174T derived from human adenocarcinoma of colon. Among the selected compounds belong roskovitin and its derivates designed as BA-12 and BP-14. Previous studies demonstrated that these substances inhibit both mentioned transporters and therefore increase the effect of simultaneously administrated cytotoxic drugs. Since the drug interactions on the level of transporters can arise from induction of their corresponding genes, the aim of this work was to extend the current knowledge on mentioned derivates of roskovitin in terms of possible affection of ABCB1 and ABCG2 expression. Enhanced expression could promote developement of multidrug resistance (MDR). Results of this work obtained with qRT- PCR method show that neither BA-12 nor BP-14 increase expression of...
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Interactions of selected antiretroviral drugs and methylmercury with placental membrane transporters
Ťupová, Lenka ; Čečková, Martina (advisor) ; Fusek, Josef (referee) ; Kacerovský, Marian (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Lenka Ťupová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of doctoral thesis: Interactions of selected antiretroviral drugs and methylmercury with placental membrane transporters. Pregnant women are especially in developed countries exposed to high amount of various xenobiotic including environmental pollutants and drugs. Antiretroviral therapy (ART) is administered to HIV positive pregnant women for the purpose of prevention of HIV mother- to-child-transmission. Pharmacokinetics of many antiretrovirals is limited or enhanced by activity of ATP-binding cassette (ABC) or Solute carrier's transporters, of which many are expressed also in placental tissue. ART therapy usually consists of combination of 3 - 4 antiretroviral drugs, thereby leading to higher risk for development of drug-drug interactions on ABC and SLC transporters. In this study we described influence of non-nucleoside reverse transcriptase inhibitors etravirin and rilpivirin on BCRP- and MDR1-mediated transport of tenofovir disoproxil fumarate (TDF) and/or abacavir. Etravirin showed potent inhibition of BCRP transporter significantly changing transport of both, TDF and abacavir, across monolayers of MDCKII-BCRP...
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Effect of CDK and FLT3 inhibitors on activity of ABC efflux transporters in vitro, relation to multidrug resistance
Poráč, Jakub ; Čečková, Martina (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Jakub Poráč Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Effect of CDK and FLT3 inhibitors on activity of ABC efflux transporters in vitro, relation to multidrug resistance P-gp and BCRP are transmembrane proteins that form part of a large family of ABC transporters. These are ATP-driven transporters, which main task is to eliminate exogenous and endogenous substances and their metabolites from cells of both, healthy and tumour tissues. This activity is often associated with the expulsion of administered therapeutics and multiple drug resistance (MDR) in tumour cells. A promising therapy of cancer represents a newer class of drugs target the tyrosine kinase (TK), and cyclin-dependent kinases (CDK), which are cell enzymes responsible for the processes of proliferation, apoptosis and differentiation. Cyclin- dependent kinase inhibitors (CDKI) are used in the treatment of breast cancer, but at the same time they form a new group of drugs with the potential for use in hematological malignancies. In the treatment of AML, a new successful approach is TK inhibitors (TKI), which target the mutated FLT3 receptor, specifically the recently approved drugs midostaurin and...
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Expression and funkction of placental drug transpoters in health and disease
Umanová, Barbora ; Čečková, Martina (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Barbora Umanová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Expression and function of placental drug transporters in health and disease There are many physiological changes during pregnancy. Placenta is a crucial organ which mediates exchange of nutrients, metabolites and respiratory gases, provides endocrine functions and fetal protection. A pregnant woman and her fetus may be exposed to various potentially harmful substances during pregnancy, including drugs that may endanger fetal health. Protection of the fetus from xenobiotics is enabled by drug transporters. Drug transporters are membrane proteins expressed in most tissues of the human body. In the placenta, they are localized in the placental syncytiotrophoblast and occur also in the endothelial cells of the fetal vessels. They belong into two large superfamilies of transporter proteins: ATB-binding cassette (ABC) and solute carrier (SLC). While ABC transporters mediate exclusively efflux of their substrates, SLC are predominantly influx transporters. Therefore, these transport proteins play a key role in the disposition of drugs, some of which facilitate drugs entry into a fetus, and others actively...
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Study on interactions of PARP inhibitors with ABC drug efflux transporters
Dziaková, Lucia ; Hofman, Jakub (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucia Dziaková Supervisor: RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Study on interactions of PARP inhibitors with ABC drug efflux transporters. ATP-binding cassette (ABC) transporters are integral membrane proteins that use the energy obtained from ATP to carry transport of numerous endogenous substrances out of the cells, but attention is drawn primarily to the fact that they transfer also xenobiotics. Their overexpression in tumor tissue contributes to multidrug resistance (MDR), which in most cases leads to therapy failure. Poly(ADP-ribose)polymerase inhibitors (PARPi) represent a promising therapeutic approach in the treatment of cancers that exhibit defects in homologous recombination (HR). This work focuses on four selected PARPi (olaparib, rucaparib, niraparib, veliparib) and their interaction potential towards ABC drug efflux transporters (ABCB, ABCC1, ABCG2). In our work, we worked with MDCKII cells (parent, transduced by the transporters of interest) and utilized the principle of accumulation studies based on the measurement of fluorescence intensity of specific model substrates (hoechst33342, calcein AM, daunorubicin, mitoxantrone). We used established inhibitors of studied...
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A study of interactions of novel anticancer drugs with drug transporters.
Šorf, Aleš ; Čečková, Martina (advisor) ; Kollár, Peter (referee) ; Froňková, Eva (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Aleš Šorf Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of doctoral thesis: A study of interactions of novel anticancer drugs with drug transporters. Despite the significant progress in recent years, the efficiency of anticancer therapy is still complicated by drug resistance. This phenomenon can be mediated by pharmacokinetic mechanisms such as efflux via ATP-binding cassette (ABC) transporters and biodegradation of parent drug to inactive metabolites via metabolizing enzymes. These proteins also play a key role in absorption, distribution and excretion of drugs. When two or more interacting substances are administered simultaneously, the pharmacokinetic drug-drug interactions may occur. Since the targeted protein kinase inhibitors are becoming more common and important component of modern anticancer therapy, the aim of this study was to elucidate interactions of selected drugs of this novel therapeutic group with ABC transporters and also drug metabolizing enzymes by in vitro approaches. We further examined relevant substances ex vivo using mononuclear cells isolated directly from the blood of patients de novo diagnosed for acute myeloid leukemia (AML). Regarding the...
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