<p>Zahvaljujući amfifilnoj strukturi i mogućnosti građenja konjugata, žučne kiseline - endogeno sintetisani produkti katabolizma holesterola su prepoznate kao potencijalni nosači lekova i promoteri transporta kroz biolo&scaron;ke membrane. Otkriće da aktivacijom specifičnih nuklearnih receptora reguli&scaron;u ekspresiju gena uključenih u plejadu signalnih puteva uključenih u metabolizam, proliferaciju i diferencijaciju ćelija i onkogenezu, pro&scaron;irilo je ulogu žučnih kiselina u odnosu na inicijalno opisanu ulogu intestinalnih emulgatora. Žučne kiseline se danas ne smatraju samo pasivnim nosačima lekova i promoterima transporta kroz biolo&scaron;ke membrane već i molekulima sa farmakodinamskom funkcijom, koji reguli&scaron;u različite aspekte integrativnog ćelijskog metabolizma. Doksorubicin je jedan od najče&scaron;će kori&scaron;ćenih antineoplastičkih agenasa i sastavna je komponenta mnogih hemoterapijskih protokola u lečenju solidnih i hematolo&scaron;kih maligniteta. Međutim, hepatotoksični i kardiotoksični efekti značajno ograničavaju upotrebu ovog, inače veoma korisnog antitumorskog agensa. Pojava odložene dozno-zavisne kardiotoksičnosti predstavlja značajan zdravstveni problem onkolo&scaron;kih pacijenata sa uspe&scaron;no lečenim malignitetom, naročito pacijenata lečenih u pedijatrijskom uzrastu. Budući da je razvoj novih lekova veoma dug i skup proces sa neizvesnim ishodom, pobolj&scaron;anje farmakodinamskih i farmakokinetskih svojstava već postojećih antitumorskih agenasa sa dokazanom efikasno&scaron;ću, uz smanjenje toksičnih efekata, predstavlja racionalan istraživački pristup u savremenoj medicini. Osnovni cilj ovog rada je ispitivanje uticaja žučnih kiselina ursodeoksiholne, henodeoksiholne i 12-okso-henodeoksiholne kiseline (12-monoketoholne kiseline) na citotoksičnu aktivnost doksorubicina prema MCF-7 ćelijskoj liniji humanog adenokarcinoma dojke i ispitivanje molekularnih mehanizama odgovornih za farmakodinamske efekte. Takođe su navedene žučne kiseline ispitane kao promoteri transporta koji utiči na prodor i kumulaciju doksorubicina u malignim ćelijama. U ovom radu je ispitan uticaj koadministracije navedenih žučnih kiselina sa doksorubicinom na odložene toksodinamske efekte (hepatotoksičnost i kardiotoksičnost) kod pacova, ali i efekti pretretmana žučnim kiselinama na koncentracije doksorubicina u krvi, bilijarnu ekskreciju leka kao i kumulaciju u jetri i miokardu eksperimentalnih životinja. Žučne kiseline su u netoksičnim koncentracijama potencirale in vitro citotoksične efekte doksorubicina na MCF-7 ćelijskoj liniji pri čemu je henodeoksiholna ispoljila sinergistički efekt, dok su ursodeoksiholna u 12-monoketoholna ispoljile aditivni citotoksični efekt sa doksorubicinom. Ispitivanjem molekularnih mehanizama citotoksičnih efekata utvrđeno je da su žučne kiseline u različitom stepenu potencirale apoptozu ćelija mitohondrijalnim putem uticajem na ekspresiju pro- i antiapoptotskih proteina na transkripcionom nivou i povećale stres endoplazmatskog retikuluma, ali i dovele do alteracija ekspresije gena koji kodiraju sintezu antioksidativnih enzima, transmembranskih efluks proteina i enzima uključenih u metaboličku inaktivaciju leka. Žučne kiseline u netoksičnim koncentracijama su takođe značajno povećale prodor i kumulaciju doksorubicina u MCF-7 ćelijskoj liniji. U in vivo sistemu, koadministracija žučnih kiselina nije rezultovala u pobolj&scaron;anju odloženih toksodinamskih efekata visokih doza doksorubicina na biohemijskom i molekularnom nivou. Međutim, nakon pretretmana žučnim kiselinama, vrednosti koncetracija doksorubicina u serumu su bile povi&scaron;ene nakon pretretmana urso- i henodeoksiholnom kiselinom i snižene nakon pretretmana 12-monoketoholnom kiselinom uz povećanje bilijarne sekrecije doksorubicina. Pored promena u farmakokinetskom profilu doksorubicina, pretretman žučnim kiselinama je blago redukovao prodor i kumulaciju doksorubicina u hepatocite i kardiomiocite. Na osnovu rezultata ove studije može se zaključiti da primena ispitivanih žučnih kiselina sa doksorubicinom povećava prodor i pobolj&scaron;ava farmakodinamski profil doksorubicina in vitro, na ćelijskom modelu humanog adenokarcinoma dojke. Pobolj&scaron;anje selektivnog preuzimanja i prodora doksorubicina u maligne ćelije koje nije praćeno povećanom kumulacijom u normalnim tkivima, kao i pobolj&scaron;anje antitumorskog dejstva doksorubicina sa mogućim smanjenjem doze uz smanjenje pojave dozno-zavisnih neželjenih dejstava doksorubicina čini žučne kiseline molekulima kandidatima za dalja ispitivanja u cilju razvoja novih, pobolj&scaron;anih antitumorskih terapijskih strategija.</p> / <p>Due to the amphiphilic structure and the significant conjugation potential, bile acids - endogenously synthesized products of cholesterol catabolism have been recognized as potential drug carriers and promoters of transport through biological membranes. The discovery that by activating specific nuclear receptors bile acids regulate the expression of genes involved in various signaling pathways including metabolism, cell proliferation and differentiation as well as carcinogenesis, expanded initially ascribed role of intestinal emulsifiers to the various fields. Bile acids are now considered not to act only as passive carriers of drugs and promoters of transport through biological membranes, but also as the molecules with pharmacodynamic activity, regulating various aspects of integrative cellular metabolism. Doxorubicin is one of the most commonly prescribed antineoplastic agents as an integral component of many chemotherapy protocols in the treatment of both solid and hematologic malignancies. However, hepatotoxic and cardiotoxic effects significantly limit the use of this, otherwise, very useful anti-tumor agent. The development of dose-dependent cardiotoxic side effects represents particular health issue in successfully treated oncological patients, especially among survivors of pediatric malignancies. Since the development of new drugs is very long and expensive process with an uncertain outcome, improving the pharmacodynamic and pharmacokinetic properties of the existing agents with proven efficacy, while reducing toxic side effects, represents a rational approach to research in modern medicine. The main objective of this work is to examine the role of bile acids: ursodeoxycholic, chenodeoxycholic and 12-oxo-chenodeoxycholic acid (12-monoketocholic acid) on the cytotoxic activity of doxorubicin in the MCF-7 human breast adenocarcinoma cell line, and to get insight on molecular mechanisms responsible for underlying pharmacodynamic effects. The capacity of bile acids to promote the transport and accumulation of doxorubicin in malignant cells was also evaluated. In addition, the effect of co-administration of the bile acids with doxorubicin on delayed toxodynamic effects (hepatotoxicity and cardiotoxicity) in rats, as well as the effects of bile acid pretreatment on the doxorubicin serum concentration and pharmacokinetic profile, biliary excretion of the drug as well as accumulation in the liver and myocardial cells of experimental animals were examined. Bile acids applied in non-toxic concentrations potentiated in vitro cytotoxic effects of doxorubicin in MCF-7 cell line. Chenodeoxycholic acid exhibited a synergistic effect, whereas ursodeoxycholic and 12-monoketocholic acid exhibited an additive cytotoxic effect with doxorubicin. By examining the underlying molecular mechanisms of cytotoxic effects, bile acids have been found to potentiate apoptosis of cells by mitochondrial-dependent pathway by modifying the expression of pro- and anti-apoptotic proteins at the transcriptional level and to increase endoplasmic reticulum stress, but also have altered the expression of genes encoding the synthesis of antioxidant enzymes, transmembrane efflux proteins and enzymes involved in metabolic inactivation of the drug. Non-toxic concentrations of bile acids also significantly increased the penetration and accumulation of doxorubicin in MCF-7 cell line. In the in vivo system, the co-administration of bile acid did not improved delayed toxodynamic effects of high dose of doxorubicin both at the biochemical and molecular levels. However, pretreatment with bile acids resulted in alterations of serum doxorubicin concentrations. Chenodeoxycholic and ursodeoxycholic acid elevated whereas 12-monoketocholic acid decreased serum doxorubicin concentrations. In addition to changing pharmacokinetic profile of doxorubicin on bile acid species-dependent manner, all bile acids have also increased excretion of drug by the biliary route, and slightly reduced penetration and accumulation of doxorubicin in hepatocytes and cardiomyocytes. Based on the results of this study, the administration of the examined bile acids with doxorubicin increases the penetration and improves the pharmacodynamic profile of doxorubicin in vitro on the cell model of human breast adenocarcinoma. The improvement of selective uptake and penetration of doxorubicin into malignant cells that is not accompanied by increased accumulation in normal tissues, as well as the improvement in the anti-tumor effects of doxorubicin with a possibility to reduce the dose and thereby the occurrence of dose-dependent undesirable effects of doxorubicin, render bile acids as the potential candidate molecules in developing novel antitumor therapeutic strategies.</p>

Objectives Main objectives of this doctoral thesis were to review available information on pharmacological properties of benzodiazepines and their age-related changes; to evaluate the prevalence of benzodiazepine use in older patients residing in long term care facilities; to investigate the association between use of benzodiazepines and occurrence of falls in acutely hospitalized older patients; and to describe utilization of benzodiazepines in the Czech Republic. Methods A narrative review of literature focused on pharmacokinetics, pharmacodynamics, adverse effects and association of benzodiazepines with falls in older population was conducted. The evaluation of benzodiazepine use in long term care facilities was analysed in a retrospective cross-sectional study using data from the EC 7th Framework Program SHELTER project (Service and Health in the Elderly in Long Term Care). A prospective cohort study data of acutely hospitalized patients in Australia were used to evaluate association between benzodiazepines and falls. To describe utilization of benzodiazepines in the Czech Republic, data from the State Institute for Drug Control and from databases of General Health Insurance Fund were used. This dissertation thesis is a summary of published articles from above stated works and analyses. Results...

This thesis examines a conversion of a solution produced by geometric semantic genetic programming (GSGP) to an instantion of cartesian genetic programming (CGP). GSGP has proven its quality to create complex mathematical models; however, the size of these models can get problematically large. CGP, on the other hand, is able to reduce the size of given models. This thesis combinated these methods to create a subtree CGP (SCGP). The SCGP uses an output of GSGP as an input and the evolution is performed using the CGP. Experiments performed on four pharmacokinetic tasks have shown that the SCGP is able to reduce the solution size in every case. Overfitting was detected in one out of four test problems.

Throughout the scientific world the topic of cannabis usage and its link with psychosis seems to be discussed intensively. Considering the fact that the Czech Republic is a country with one of the highest prevalence of cannabis usage in the world it becomes a sensitive issue even in our circumstances. In the theoretical part of the work we attempted to review current knowledge of a link between cannabinoid system, canabis usage and psychosis and to point out possible future therapeutic potential of cannabinoids in the treatment of psychotic diseases. In the practical part of the work we focused on verification of propsychotic features of THC in animal model with particular attention to validation of acute subcutaneous admonistration of this drug as a novel cannabinoid model of psychosis. At the same time we tried to elucidate antipsychotic effect of CBD in this model. We tested these hypotheses in two behavioral tests (open field test, PPI ASR) and electrophysiologically (quantitative EEG). The whole analysis is enriched with pharmacokinetic data from subcutanneous and oral administration of cannabinoids. Powered by TCPDF (www.tcpdf.org)

Charles University Faculty of Pharmacy in Hradec Kr'alov'e Department of Biophysics and Physical Chemistry Candidate: Yestay Rakhimov Supervisor: doc. Erik Jurjen Duintjer Tebbens, Ph.D. Title of diploma thesis: Mathematics and implementations of physiologically based phar- macokinetic modeling The thesis addresses some basic aspects of pharmacokinetic modeling, which is used to describe pharmacokinetic processes. Understanding these processes is important for example to determine optimal concentrations of drugs dosing. The thesis focuses on mathematical proofs of a number of pharmacokinetic equa- tions, which are often not given in standard books. The derived equations are illustrated with numerical experiments for a particular drug in the software PharmCalcCl and MAT- LAB. 4

Objectives Main objectives of this doctoral thesis were to review available information on pharmacological properties of benzodiazepines and their age-related changes; to evaluate the prevalence of benzodiazepine use in older patients residing in long term care facilities; to investigate the association between use of benzodiazepines and occurrence of falls in acutely hospitalized older patients; and to describe utilization of benzodiazepines in the Czech Republic. Methods A narrative review of literature focused on pharmacokinetics, pharmacodynamics, adverse effects and association of benzodiazepines with falls in older population was conducted. The evaluation of benzodiazepine use in long term care facilities was analysed in a retrospective cross-sectional study using data from the EC 7th Framework Program SHELTER project (Service and Health in the Elderly in Long Term Care). A prospective cohort study data of acutely hospitalized patients in Australia were used to evaluate association between benzodiazepines and falls. To describe utilization of benzodiazepines in the Czech Republic, data from the State Institute for Drug Control and from databases of General Health Insurance Fund were used. This dissertation thesis is a summary of published articles from above stated works and analyses. Results...

<p>Uvod: U pro&scaron;losti žučne kiseline su uglavnom razmatrane sa stanovi&scaron;ta njihove funkcije koju obavljaju u crevima jer posreduju u varenju masti i apsorpciji liposolubilnih vitamina. Nedavne studije potvrđuju da žučne kiseline ne igraju samo ulogu u varenju masti, nego se pona&scaron;aju i kao signalni molekuli koji stupaju u interakciju sa raznim receptorima uključujući nuklearne receptore i receptore vezane za G-proteine. Kao amfipatični molekuli one su sposobne da reaguju sa fosfolipidima ćelijskih membrana i da pobolj&scaron;avaju prolazak lekova kroz njih. Stoga se žučne kiseline razmatraju kao promoteri u bukalnim, okularnim i nazalnim farmaceutskim formulacijama. Cilj: Svrha ovog istraživanja je bila da se ispitaju žučne kiseline i njihovi okso derivati kao jedinjenja koja utiču na propustljivost ćelijskih membrana i prolazak lekova do ciljnih tkiva. Materijal i metod: Interakcije makrolidnih antibiotika i žučnih kiselina su ispitivane uz pomoć NMR difuzionih merenja i relaksacije paramagnetičnim jonima. Retencioni parametri odabranih žučnih kiselina su dobijeni kori&scaron;ćenjem hromatografije na normalnim fazama i evaluisani su primenom pet različitih softvera. In vivo ekaperimenti su sprovedeni na 126 eksperimentalnih životinja koje su bile podeljene u 21 grupu. Rezultati: Vezivanje žučnih kiselina za micele je indikovano razlikama u hemijskom pomeranju makrolida i pro&scaron;irenju signala kao posledica redukovane mobilnosti unutar micela. Dodatak micela žučnih kiselina povećava solubilizaciju makrolida za faktor približno 2-3. Sprovedena korelaciona analiza pokazala je značajnu zavisnost između faktora retencije i intestinalne apsorpcije, prodora u MDCK epitelne ćelije, permeabilnost kroz kožu, logBB i PPB%. Putem implementacije in vivo eksperimentalnog dela pokazano je da žučne kiseline utiču na prolazak makrolida u tkivo mozga, bubrega i jetre. Zaključak: Ispitivane žučne kiseline pokazuju dobre farmakokinetske karakteristike i olak&scaron;avaju prolazak makrolida kroz različite ćelijske membrane.</p> / <p>Introduction: In the past, bile acids were mostly considered to function in the intestine where they play a role in digestion of fats and mediate absorption of fat-soluble vitamins. Recent studies confirm that bile acids not only facilitate solubilization of fats but behave as signal molecules that interact with various receptors including nuclear receptors and G protein-coupled receptors. As amphipathic molecules they are able to interact with phospholipids of cells membranes and enhance drugs permeation. Thus, bile acids are considered as drug promoters in buccal, ocular, nasal, and transdermal dosage forms. Purpose: The purpose of this research was to investigate bile acids and its oxo derivatives as enhancers in drug permeability. Three research methods to evaluate the characteristics of bile acids and its properties were used. Material and method: The interaction between macrolide antibiotics and bile acids was investigated by NMR chemical-shift titration, self-diffusion measurements and paramagnetic relaxation enhancements. Retention parameters of selected bile acids are acquired by normal-phase thin layer chromatography and evaluated using five different softwares. In vivo experiments were conducted on 126 animals which were divided in 21 groups. Results: Binding bile acids to the micelles is indicated by differences in the chemical shift of the macrolides and line broadening as a consequence of reduced mobility in the micelle. Addition of bile micelles increases the solubility of macrolide antibiotics by a factor of approximately 2&ndash;3. Examined correlation analysis confirmed significant dependence between retention factor and intestinal absorption, MDCK epithelial cells, skin permeability, logBB and PPB%. Through the implementation of in vivo experiments it is shown that bile acids promote penetration of macrolides in brain tissue, kidney and liver. Conclusion: Investigated bile acids showed good pharmacokinetic properties and facilitate in macrolides permeation through various membranes.</p>

<p>Poslednjih godina je prisutan trend povratka prirodi i upotrebi biljnih lekova, kako u prevenciji tako i u lecenju razlicitih bolesti. Timijan (Thymus vulgaris L.) se u narodnoj medicini koristio u lecenju respiratornih oboljenja kao &scaron;to su ka&scaron;alj, bronhitis i astma. Rezultati novijih istraživanja pokazuju da timijan poseduje i druga potencijalno korisna farmakolo&scaron;ka svojstva (antimikrobna, antiinflamatorna, antioksidativna, spazmoliticka, antidijabetesna i anksioliticka). Ciljevi ovog istraživanja su bili da se ispitaju farmakodinamske osobine preparata timijana, njihove interakcije sa lekovima koji deluju na centralni nervni sistem, uticaj na funkciju jetre i parametrem oksidativnog stresa kod životinja izloženih ugljentetrahloridu, kao sadržaj karvakrola i timola u sirupu timijna, pri razlicitim uslovima cuvanja. U farmakodinamskim ispitivanjima kao eksperimentalne životinje kori&scaron;ceni su mi&scaron;evi soja NMRI, a u svim drugim ispitivanjima pacovi soja Wistar. Tinktura timijana je primenjena u dozi od 0,4mk/kg, a sirup u dozi od 12,08 ml/kg, na mi&scaron;evima. Primenjene doze na pacovima su bile 0,18 ml/kg za tinkturu i 5,6 ml/kg za sirup timijana. Za ispitivanje analgetickog dejstva kori&scaron;ceni su metod vrele ploce i test sircetne kiseline. Za procenu motorne koordinacije kori&scaron;cen je test rotirajuceg &scaron;tapa, a za procenu hipnotickog delovanja mereno je vreme spavanja. Prilikom ispitivanja uticaja preparata timijana na farmakokinetiku paracetamola, odre_ivana je koncentracija ovog leka HPLC metodom, a nakon toga su odreeni farmakokinetski parametri paracetamola. Antioksidantna aktivnost preparata timijana odre_ivana je pomocu in vitro i in vivo testova. Nakon žrtvovanja životinja ra_ena je histopatolo&scaron;ka analiza jetrenog tkiva, a u serumu su odre_ivani biohemijski parametri, kao i pokazatelji bubrežene i jetrene funkcije. Sadržaj timola i karvakrola i sirupu timijana odre_en je GC/MS metodom. Sirup i tinktura timijana su pokazali analgeticki efekat u testu vrele ploce, kao i smanjenje broja grceva izazvano primenom sircetne kiseline. Sedmodnevna primena preparata timijana smanjila je analgeticko dejstvo kodeina, a pojacala analgeticki efekat paracetamola. Sirup timijana je potencirao diazepamom izazvan poremecaj motorne koordinacije. Ispitivanjem uticaja preparata timijana na hipnoticko delovanje pentobarbitala, postignuti su razliciti rezultati u zavisnosti od dužine trajanja pretremana. Sedmodnevna primena timijana je produžila vreme trajanja spavanja, dok je jednokratna primena timijana skratila vreme trajanja spavanja. Nakon i intravenske i peroralne primene paracetamola, grupe životinja koje su bile pretretirane preparatima timijana imale su krace poluvreme eliminacije i vecu konstantu eliminacije. Upotreba samo preparata timijana nije imala uticaj na biohemijske i histolo&scaron;ke promene jetrene funkcije. S druge strane, upotreba tincture timijana u kombinaciji sa ugljen-tetrahloridom dovela je do porasta vrednosti AST i ALT enzima u serumu, dok je sirup timijana u kombinaciji sa ugljentetrahloridom smanjio aktivnost aminotransferaza. Najvece odstupanje u koncentracijama aktivnih komponenti timola i karavkrola, pokazali su sirupi cuvani na sobnoj temperaturi (20&deg;C), u sekundarnoj ambalaži i na svetlom mestu. Rezultati dobijeni u toku ovog istraživanja ukazuju da preparati timijana uticu na farmakodinamske osobine kodeina, paracetamola, diazepama i pentobarbitala, kao i na farmakokinetiku paracetamola. Upotreba preparata timijana ispoljila je analgeticki efekat i umanjila posledice izloženosti oksidativnom stresu. Uslovi cuvanja sirupa timijana uticali su na njegovu stabilnost.</p> / <p>In recent years is present trend of return to nature and the use of herbal medicines in prevention and treatment of different diseases. Thyme (Thymus vulgaris L.) was used in folk medicine in the treatment of respiratory diseases such as cough, bronchitis and asthma. The new research results have demonstrated that thyme has many others potentially useful pharmacological properties (antimicrobial, antiinflammatory, antioxidant, antispasmodic, antidiabetic and anxiolytic). The aims of this research were to determine the pharmacodynamic properties of thyme preparations and their interactions with central nervous system drugs, influence on liver function and oxidative stress parameters of animals exposed to carbon tetrachloride, as well as concentration of thymol and carvacrol in thyme syrup, at different storage conditions. In pharmacodynamics examination as experimental animals were used NMRI mice, while in all other test were used Wistar rats. Applied dose of thyme tincture was 0.4 ml/kg and of syrup 12.08 ml/kg, for mice. For rats, applied doses of tincture and syrup were 0.18 ml/kg and 5.6 ml/kg, respectively. The analgesic activity was examined by the hot plate test and acetic acid test. The Rotarod test was used to evaluate the motor coordination and to evaluate hypnotic activity sleeping time was mesaured. In order to examine the influence of thyme preparations on pharmacokinetics of paracetamol, the concentracion of this drug was measured by HPLC metods, and after that pharmocokinetic parameters of paracetamol were determined.The antioxidant acivity of thyme preparations was determined by using in vitro and in vivo tests. After animals sacrificing, histopathological analysis of liver tissue were peroformed, in serum were determined biochemical parameters and renal and hepatic function parameters. Quantification of thymol and carvacrol in syrup was carried out by GC/MS method. Thyme syrup and thyme tincture exhibited analgesic activity in hot plate test and reduced the number of writhes induced by acetic acid. Seven-day pretreatment with thyme preparations reduced analgesic activity of codeine and increased analgesic effect of paracetamol. Thyme syrup potentiated diazepam induced motor coordination impairment. Examining the impact of thyme preparations on hypnotic effect induced by pentobarbital, different results were achieved depending on the duration of pretreatment. Seven-day pretreatment with thyme had prolonged the sleeping time, while after single dose of thyme the sleeping time was decreased. After intravenous and after oral administration of paracetamol, groups pretreated with thyme preparations had decreased elimination half-life and increased elimination constant rate. Administration of thyme preparations alone did not change biochemical nor histological markers of hepatic function. On the other hand, co-administration of thyme tincture and carbon tetrachloride resulted in exacerbation of AST and ALT values in serum, while thyme syrup in coadministration with carbon tetrachloride managed to reduce activities of aminotransferases. The concentration of major active compounds, thymol and carvacrol, was mostly changed when syrups were stored at room temperature (20&deg;C), in secondary containers and in light place. Results obtained in this study demonstrated that thyme preparations do affect pharmacodynamic properties of codeine, paracetamol, diazepam and pentobarbital and pharmacokinetics of paracetamol. Administration of thyme preparations exhibited analgesic activity and reduced the effects of exposure to oxidative stress. Storage conditions of thyme syrup did affect its stability.</p>

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Křečková Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Role of drug transporters in placental transfer of entecavir Entecavir (ETV), an analogue of guanosine, is a highly efficient anti-hepatitis B antiviral drug. It is the first-line therapy for both adults and children. Its use in pregnancy is limited due to a number of factors, including lack of data on placental pharmacokinetics. The placental transition of drugs is frequently controlled by drug transporters. ATP-binding (ABC) transporters, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) or multidrug resistance-associated protein 2 (MRP2) localized in the apical membrane of syncytiotrophoblast and pumping their substrates in the feto-maternal direction belong to most significant determinants of placental pharmacokinetics. Moreover placental transport of nucleoside-derived drugs can be affected by the activity of nucleoside transporters (NTs); equilibrative nucleoside transporters (ENTs) mediate facilitated diffussion, while the concentrative nucleoside transporters (CNTs) control active influx of their substrates. The aim of the diploma thesis was to describe the role of P-gp, BCRP, MRP2 and NTs (ENTs and...

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...