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Variability of pharmacokinetics and possibilities for its monitoring.
Světlík, Svatopluk ; Slanař, Ondřej (advisor) ; Čabala, Radomír (referee) ; Paluch, Zoltán (referee)
Backgroun and aims: Pharmacokinetic variability is of paramount importance for sucessfull pharmacotherapy. The main purpose of this work was to study variability of pharmacokinetics in clinical and non-clinical setting with the aim to predict variability in target population. Specifically, three drugs were chosen, sufentanil, with relativelly narrow therapeutic index, and nabumeton and abirateron, both with known high variability. Methods: The study of pharmacokinetic variability of sufentanil was based on clinical samples taken from patients undergoing surgical cardiac procedure, where the sufentanil was used as a part of the drug coctail used during the procedure. New analytical method was necessary to prepare and validate to measure sufentanil concentrations and obtain pharmacokinetic parameters. These were compared between determined genotype groups of MDR1 and OPRM1. Similarly, clinical study was executed with nabumetone, in which nabumetone was administered in a group of 24 subjects on two separate occassions. Plazma samples were obtained and concentrations of nabumetone and its active metabolite, 6-methoxynaphtylacetic acid (6-MNA), were determined. Obtained pharmacokinetic profiles were compared between female and male volunteers, and genotypes for MDR1 and CYP2D6. Finaly for abiraterone,...
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Polymorphism of drug metabolizing enzymes as a potential target of prevention of serious treatment complications in neonates and infants
Hronová, Karolína ; Slanař, Ondřej (advisor) ; Paluch, Zoltán (referee) ; Hladík, Michal (referee)
Univerzita Karlova 1. lékařská fakulta Studijní program: Biomedicína Studijní obor: Preventivní medicína MUDr. Karolína Hronová Polymorfismus genů účastnících se v metabolismu léčiv jako potenciální cíl prevence závažných komplikací léčby u novorozenců a dětí Polymorphism of drug metabolizing enzymes as a potential target of prevention of serious treatment complications in neonates and infants Disertační práce- ABSTRAKT V ANGLICKÉM JAZYCE Školitel: prof. MUDr. Ondřej Slanař, Ph.D. Konzultant: MUDr. Pavla Pokorná, PhD. Praha, 2018 Abstract Background and aims: The safety of analgosedative drugs includes drug interactions, adverse effects, withdrawal syndrome and drug dependence are factors that significantly affect morbidity and mortality. Its prevention is critical for quality improvement of care in paediatric patients. The aim of the thesis was to evaluate the prediction of efficacy and safety of analgosedative drugs sufentanil, midazolam, tramadol and valproic acid in neonates and children based on the occurrence of selected pharmacogenetic biomarkers. The incidence of drug interactions of phenobarbital with other analgosedative drugs has also been evaluated. Methodology: The thesis is based on two studies conducted on Intensive and Resuscitation Care Unit of the Clinic of Paediatric and Adolescent...
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Effect of epigallocatechin gallate on bile production
Hiršová, Petra ; Čečková, Martina (advisor) ; Trejtnar, František (referee) ; Slanař, Ondřej (referee)
Effect of epigallocatechin gallate Epigallocatechin gallate (EGCG), the major green tea catechin, has been shown to be protective in various experimental models of liver injury. Since its effect on biliary physiology and liver cholesterol homeostasis has not been thoroughly studied, the present study investigated effect of EGCG on bile flow, bile acid homeostasis and cholesterol metabolism in healthy and ethinylestradiol-treated rats. Compared to controls, EGCG treatment in rats decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by EGCG administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter at the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. Interestingly, EGCG markedly enhanced biliary excretion of cholesterol and phospholipids. These changes tightly correlated with increased expression of ATP- binding cassette transporter G5 and G8 (Abcg5/8) and scavenger receptor class B type 1 and with decreased expression of acyl-CoA:cholesterol acyltransferase (Acat2). EGCG administration to rats also doubled plasma bile acid concentrations compared to controls. While protein expression of the main...
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Factors affecting drug distribution and elimination and their application in personalized pharmacotherapy.
Šíma, Martin ; Slanař, Ondřej (advisor) ; Juřica, Jan (referee) ; Tesfaye, Hundie (referee)
The aim of this dissertation thesis was to study the factors affecting drug distribution and elimination and to use these factors to individualize dosing. The work consists of three thematic areas: estimation of the volume of distribution and subsequent dosing of selected drugs (vancomycin, amikacin, phenobarbital) using body size descriptors; estimation of clearance and subsequent dosing of selected drugs (vancomycin, amikacin, phenobarbital, perindopril) using renal function status markers; and the impact of drug interactions on the distribution and elimination of phenobarbital. The thesis summarizes original papers on these topics. Individual pharmacokinetic parameters were calculated for each patient based on their demographic and clinical characteristics, dosing records and measured serum drug levels. The relationships between distribution volume/drug clearance and body size descriptors/renal functional status markers were examined by regression analysis. Vancomycin volume of distribution was best predicted by the total body weight. Loading dose of 10.7 mg/kg of total body weight was optimal in patients taking continuous vancomycin and would lead to reducing of median time to reach target concentrations from 17 to 1 hour. On the contrary, amikacin volume of distribution was most associated...
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Pharmacogenetic prediction of tamoxifen efficiacy and adverse effects in hormonal dependent breast karcinoma patients.
Argalácsová, Soňa ; Slanař, Ondřej (advisor) ; Vrána, David (referee) ; Paluch, Zoltán (referee)
ABSTRACT/SUMMARY Background: The clinical efficacy of tamoxifen therapy may be modified by the drug-metabolizing enzymes and transporting molecules involved into the pharmacokinetics of tamoxifen. The aim of this study was to evaluate the association of CYP2D6, ABCB1 polymorhisms and comedication with efficacy and safety of tamoxifen treatment. Methods: Totally 258 women with hormonal positive breast carcinoma were retrospectively evaluated in relation to CYP2D6, ABCB1 polymorphisms and comedication. Results: CYP2D6 polymorphisms or co-medication affecting CYP2D6 activity demonstrated no statistically significant effect on the efficacy of tamoxifen therapy or adverse event incidence; there was only a trend towards shortening the time to event (TTE) in CYP2D6 poor metabolizers. ABCB1 polymorphism rs2032582 was not associated with clinical outcomes, while a trend towards an increase of TTE in variant allele carriers was noted. The ABCB1 polymorphism rs1045642 demonstrated statistical significance in premenopausal patients (p = 0.0012, HR 0.69 (95% CI 0.21 to 2.31), and its significant association was noted with gynaecological /vasomotor adverse events (p = 0.0221, HR = 1.0588), with no evidence of the influence on the incidence and onset of venous complications. Conclusions: Although this work did not show...
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Effect of epigallocatechin gallate on bile production
Hiršová, Petra ; Mičuda, Stanislav (advisor) ; Slanař, Ondřej (referee) ; Trejtnar, František (referee)
Effect of epigallocatechin gallate Epigallocatechin gallate (EGCG), the major green tea catechin, has been shown to be protective in various experimental models of liver injury. Since its effect on biliary physiology and liver cholesterol homeostasis has not been thoroughly studied, the present study investigated effect of EGCG on bile flow, bile acid homeostasis and cholesterol metabolism in healthy and ethinylestradiol-treated rats. Compared to controls, EGCG treatment in rats decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by EGCG administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter at the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. Interestingly, EGCG markedly enhanced biliary excretion of cholesterol and phospholipids. These changes tightly correlated with increased expression of ATP- binding cassette transporter G5 and G8 (Abcg5/8) and scavenger receptor class B type 1 and with decreased expression of acyl-CoA:cholesterol acyltransferase (Acat2). EGCG administration to rats also doubled plasma bile acid concentrations compared to controls. While protein expression of the main...
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The study of the potential importance of pravastatin in the prevention of the cholestatic liver impairment
Karlasová, Gabriela ; Mičuda, Stanislav (advisor) ; Slanař, Ondřej (referee) ; Večeřa, Rostislav (referee)
The study of the potential importance of pravastatin in the prevention of the cholestatic liver impairment. Obstructive cholestasis is a clinical syndrome accompanying numerous liver diseases. Early diagnosis and appropriate treatment of obstructive jaundice is very important because untreated condition leads to irreparable changes in the liver. This gives rise to liver fibrosis, which later passes into biliary cirrhosis with all its consequences (portal hypertension, esophageal varices, liver failure). The causal therapy such as surgical removal of the obstruction is quite often impossible. Therefore it is necessary to search for pharmacotherapeutic approaches that can positively modulate the developing disease. In the present thesis, the effect of pravastatin on the liver damage during chronic obstructive cholestasis was investigated in rats. Pravastatin, belonging to a group of widely used inhibitors of HMG-CoA reductase, possesses not only lipid-lowering action but also anti-inflammatory and antioxidant effects, so called pleiotropic effects. The decisive fact for choosing pravastatin as a suitable substance for our study was that pravastatin has already shown positive effects in several patients with cholestasis and its hydrophilic nature does not require metabolism in impaired liver and allows...
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The study of the potential importance of pravastatin in the prevention of the cholestatic liver impairment
Karlasová, Gabriela ; Mičuda, Stanislav (advisor) ; Slanař, Ondřej (referee) ; Večeřa, Rostislav (referee)
The study of the potential importance of pravastatin in the prevention of the cholestatic liver impairment. Obstructive cholestasis is a clinical syndrome accompanying numerous liver diseases. Early diagnosis and appropriate treatment of obstructive jaundice is very important because untreated condition leads to irreparable changes in the liver. This gives rise to liver fibrosis, which later passes into biliary cirrhosis with all its consequences (portal hypertension, esophageal varices, liver failure). The causal therapy such as surgical removal of the obstruction is quite often impossible. Therefore it is necessary to search for pharmacotherapeutic approaches that can positively modulate the developing disease. In the present thesis, the effect of pravastatin on the liver damage during chronic obstructive cholestasis was investigated in rats. Pravastatin, belonging to a group of widely used inhibitors of HMG-CoA reductase, possesses not only lipid-lowering action but also anti-inflammatory and antioxidant effects, so called pleiotropic effects. The decisive fact for choosing pravastatin as a suitable substance for our study was that pravastatin has already shown positive effects in several patients with cholestasis and its hydrophilic nature does not require metabolism in impaired liver and allows...
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Intracellular Concentration of Methotrexate in Erytrocytes and MTHFR Polymorphisms: Possible Association with Methotrexate Efficasy and Toxicity in Patients with Juvenile Idiopathic Arthritis
Tuková, Jana ; Doležalová, Pavla (advisor) ; Slanař, Ondřej (referee) ; Pavelka, Karel (referee)
Objective: To investigate whether methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and erythrocyte concentration of methotrexate (EMTX) could serve as predictors of methotrexate (MTX) efficacy and toxicity in patients with juvenile idiopathic arthritis (JIA). Methods: Genetic analyses and EMTX and folate assessment were performed in 69 JIA patients treated with MTX and classified as full responders (n=51, disease inactivity) or nonresponders (n=18, less than 30 % improvement in paediatric ACR30 criteria while on 15 mg/m2/week parenteral MTX for at least 3 months). Results: Nonresponders were treated with the higher median MTX dose (17.2 vs 12.6 mg/m2/week, P<0.0001), and accumulated more EMTX (217 nmol/L vs 106 nmol/L, P<0.02) and erythrocyte folates (763 nmol/L vs 592 nmol/L, P=0.052) than responders. Analysis of MTHFR allele and genotype frequencies in relation to response failed to detect association. The frequency of any adverse effect was 29.4 % in responders and 33.3 % in nonresponders (P=0.77). The frequency of 677T allele was elevated in patients with adverse effects (52.4 % vs 20.9%, OR=3.88; 95% CI: 1.8-8.6; p<0.002). The probability of any adverse effect was significantly higher in patients with 677TT when compared to 677CC genotype (OR=55.5; 95-% CI: 2.9-1080;...
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Applications of chiral and achiral chromatography in pharmacology and toxicology
Chytil, Lukáš ; Slanař, Ondřej (advisor) ; Bultas, Jan (referee) ; Coufal, Pavel (referee)
Development and validation of methods for analysis of several drugs or their metabolites are decribed in this thesis. The document is presented as a commentary to the original papers, which were published in peer reviewed journals. Discussion on the optimization of each method is presented and covers also method development and influence of preanalytical aspects. Additionally, examples of the application of the developed methods in clinical pharmacology and toxicology are shown. This dissertation consists of three parts: enantiomeric determination of tramadol and its metabolite, determination of some antihypertensive drugs, and qualitative analysis of benzodiazepines. Development of a method for chiral analysis of tramadol and its desmethylated metabolite O- desmethyltramadol (ODT) in human urine and plasma is described in the first part of the thesis. Tramadol is a centrally acting analgetic drug, which is used as racemate in clinical practise. Each enantiomer displays different binding properties for various receptors: (+)-tramadol preferentially inhibits serotonin reuptake while (-)-tramadol mainly inhibits noradrenalin reuptake. (+)-tramadol is considered 10-times more potent than (-)-tramadol. Major active metabolite (ODT), which is considered to be the main agent responsible for the...
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