Dissertations / Theses: 'Pharmacokinetics. Drugs Chiral drugs'

1

Mashile, Tumelo Rameleko. "Enantioanalysis of pharmaceutical compounds." Pretoria : [s.n.], 2005. http://upetd.up.ac.za/thesis/available/etd-02222007-195248.

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Eriksson, Tommy. "Pharmacokinetics of the enantionmers of thalidomide." Malmö : Lund : Malmö University Hospital ; Lund University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/68945032.html.

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3

Karlsson, Louise. "P-glycoprotein and chiral antidepressant drugs : Pharmacokinetic, pharmacogenetic and toxicological aspects." Doctoral thesis, Linköpings universitet, Klinisk farmakologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-76126.

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The blood-brain barrier (BBB) is formed by the capillary endothelial cells, joined together by tight junctions, with transporter proteins. BBB acts to regulate the brain concentrations of substances including many drugs. Transport across the cells is necessary for a drug to ensure that the drug reaches the site of action and transport proteins such as P-glycoprotein (P-gp; ABCB1) can limit the entrance into various tissues, including the brain. Molecules that are not superimposable on their mirror images and thus exist in two enantiomeric forms (enantiomers) are said to be chiral. A racemic compound is one composed of a 50:50 mixture of two enantiomers, S- and R-enantiomers. Two examples of frequently prescribed racemic drugs are the chiral antidepressants venlafaxine (VEN) and citalopram (CIT). The enantiomers of VEN possess different pharmacodynamic profiles where the R-enantiomer is a potent inhibitor of both serotonin and noradrenaline reuptake (SNRI), while the S-enantiomer is more selective in inhibiting serotonin reuptake (SSRI). The SSRI effect of CIT resides in the S-enantiomer, whereas the R-enantiomer is considered to be therapeutically inactive, or even that it counteracts the effects. The S-enantiomer of CIT is now available as a separate SSRI (escitalopram, EsCIT). VEN and CIT are also among the most commonly found drugs in forensic autopsy cases. Few previous studies have examined a possible enantioselective activity of P-gp. Thus, the general aim of this thesis was to study the enantiomeric distribution of chiral antidepressant drugs, focusing on the role of P-gp in the BBB. For this purpose, a mouse model disrupted of the genes coding for P-gp (abcb1ab (-/-) mice) was used. Brain and serum concentrations of the enantiomers of VEN and CIT, and their major metabolites, were compared to the corresponding wild-type mice (abcb1ab (+/+) mice). The open-field locomotor and rearing activities were examined after chronic VEN administration. In addition to the animal studies, genetic and toxicological aspects of P-gp were studied in a forensic autopsy material, where intoxication cases were compared with cases that were not related to intoxications. The brain to serum concentration ratios for VEN, CIT and EsCIT differed between knockout mice and wild-type mice, with 2-3 fold higher brain concentrations in mice with no expression of P-gp. Hence, all studied drugs, and their major metabolites, were substrates for P-gp. There was no evidence for a stereoselective P-gp mediated transport. The P-gp substrate properties were reflected in the open-field behavior test where the knockout mice displayed increased center activity compared with wild-type mice following chronic VEN exposure. The genotype distribution of ABCB1 SNPs C1236T, G2677T and C3435T in VEN positive cases was significantly (or borderline) different between the intoxication cases and the non-intoxication cases. This difference in genotype distribution was not observed for the CIT positive cases. To conclude, the present work has led to an increased knowledge about how the enantiomers of VEN and CIT are affected by the BBB transporter P-gp. Using an animal model, VEN and CIT have proved to be actively transported out of the brain by P-gp and no difference was observed for the enantiomers with regard to P-gp transport. Further, the ABCB1 genotype distribution was different in intoxication cases compared with non-intoxication cases. Taken together, these findings offer the possibility that the expression of P-gp in humans may be a contributing factor for limited treatment response and increased risk of side-effects following antidepressant drug treatment.

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Olsén, Lena. "Drugs in horses : pharmacokinetics and pharmacodynamics /." Uppsala : Dept. of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, 2007. http://epsilon.slu.se/200737.pdf.

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Song, Di. "Bladder tissue pharmacokinetics of anticancer drugs /." The Ohio State University, 1996. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487940308433249.

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James, Devona Gwen. "The degradation of drugs in formaldehyde." Morgantown, W. Va. : [West Virginia University Libraries], 1999. http://etd.wvu.edu/templates/showETD.cfm?recnum=1149.

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Thesis (M.S.)--West Virginia University, 1999.
Title from document title page. Document formatted into pages; contains xvi, 100 p. : ill. Vita. Includes abstract. Includes bibliographical references (p. 98-99).

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Reis, Margareta. "Pharmacokinetics of antidepressant drugs : naturalistic and clinical trials /." Linköping : Univ, 2003. http://www.bibl.liu.se/liupubl/disp/disp2003/med783s.pdf.

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Hammann, Felix. "Prediction of transport, pharmacokinetics, and effect of drugs /." Basel : [s.n.], 2009. http://edoc.unibas.ch/diss/DissB_8905.

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Layton, Sherry E. "Comparison of various chiral stationary phases for the chromatographic separation of chiral pharmaceuticals /." Electronic version (PDF), 2005. http://dl.uncw.edu/etd/2005/laytons/sherrylayton.pdf.

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Zhang, Jing Lu. "Big data analysis of solid dispersion researches from 1980 to 2015." Thesis, University of Macau, 2018. http://umaclib3.umac.mo/record=b3952169.

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Patel, Fathima. "The development and assessment of a generic carbamazepine sustained release dosage form." Thesis, Rhodes University, 2006. http://eprints.ru.ac.za/1339/.

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Winkler, Julia. "Pharmacokinetics and pharmacodynamics of corticosteroid prodrugs and soft drugs." [Gainesville, Fla.] : University of Florida, 2004. http://purl.fcla.edu/fcla/etd/UFE0006942.

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Thesis (Ph.D.)--University of Florida, 2004.
Typescript. Title from title page of source document. Document formatted into pages; contains 157 pages. Includes Vita. Includes bibliographical references.

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Skeith, Kenneth J. "The clinical pharmacokinetics of 2-arylpropionic nonsteroidal antiinflammatory drugs." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0017/NQ46920.pdf.

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Chigutsa, Emmanuel. "Population pharmacokinetics and pharmacokinetic-pharmacodyamic modeling of antitubercular drugs." Doctoral thesis, University of Cape Town, 2013. http://hdl.handle.net/11427/3275.

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Includes abstract.
Includes bibliographical references.
The pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol in 78 patients with tuberculosis were described using non-linear mixed effects modeling. Pharmacodynamic data was comprised of weekly sputum liquid culture (using mycobacterial growth indicator tubes) time to detection results from 144 patients during the first 2 months of treatment. The effect of drug exposure on patient outcomes was investigated. To determine the adequacy of ofloxacin drug exposure, the probability of attaining the required area-under-the-curve to minimum inhibitory concentration ratio (AUC/MIC) of ofloxacin was determined in 65 patients on treatment for multidrug resistant tuberculosis. To improve efficiency in the clinical development of new drug regimens, clinical trial simulation was used to determine the optimal study design for a study investigating the efficacy of a new antitubercular drug regimen. The SLCO1B1 rs4149032 polymorphism existed at a high frequency of 0.70 in South Africans and resulted in a 28% decrease in bioavailability of rifampicin. The rifampicin peak concentration was a significant predictor of the 2 month treatment outcomes. A semimechanistic time to event model was developed to analyze days to positivity (time to detection) data. The model was comprised of a biexponential decay model describing bacillary decline in sputum from patients, followed by a logistic model with a lag time for growth of the mycobacteria in liquid culture. For the current 800 mg daily dose of ofloxacin, the probability of attaining an AUC/MIC target ratio of at least 100 was only 0.45. Based on clinical trial simulation, the optimum parallel study design was comprised of 125 study participants in each of 2 arms to achieve a study power of at least 80%. Increasing the study length beyond 42 days reduced study power perhaps due to increased amounts of censored data. Higher doses of rifampicin are required in the majority of South African patients with tuberculosis. A novel pharmacodynamic model of tuberculosis treatment is presented, which can be used for investigation of covariates such as drug exposure. Ofloxacin should be replaced with a more potent fluoroquinolone for treatment of multidrug resistant tuberculosis. Clinical trials should not be unduly long otherwise this may compromise study power.

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Kloprogge, Frank Lodewijk. "Pharmacokinetics and pharmacodynamics of antimalarial drugs in pregnant women." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:79ce1a37-3ba2-45e4-9f80-0692a66837f1.

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Malaria is the most important parasitic disease in man and it kills approximately 2,000 people each day. Pregnant women are especially vulnerable to malaria with increased incidence and mortality rates. There are indications that pregnancy alters the pharmacokinetic properties of many antimalarial drugs. This is worrisome as lower drug exposures might result in lowered efficacy and lower drug exposures can also accelerate the development and spread of resistant parasites. The aim of this research was to study the pharmacokinetics and pharmacodynamics of the most commonly used drugs for the treatment of uncomplicated Plasmodium falciparum malaria during the second and third trimester of pregnancy using a pharmacometric approach. This thesis presents a number of important findings that increase the current knowledge of antimalarial drug pharmacology and that may have an impact in terms of drug efficacy and resistance. (1) Lower lumefantrine plasma concentrations at day 7 were evident in pregnant women compared to that in non-pregnant patients. Subsequent in-silico simulations with the final pharmacokinetic-pharmacodynamic lumefantrine/desbutyl-lumefantrine model showed a decreased treatment failure rate after a proposed extended artemether-lumefantrine treatment. (2) Dihydroartemisinin exposure (after intravenous and oral administration of artesunate) was lower during pregnancy compared to that in women 3 months post-partum (same women without malaria). Consecutive in-silico simulations with the final model showed that the underexposure of dihydroartemisinin during pregnancy could be compensated by a 25% dose increase. (3) Artemether/dihydroartemisinin exposure in pregnant women was also lower compared to literature values in non-pregnant patients. This further supports the urgent need for a study in pregnant women with a non-pregnant control group. (4) Quinine pharmacokinetics was not affected by pregnancy trimester within the study population and a study with a non-pregnant control group is needed to evaluate the absolute effects of pregnancy. (5) Finally, a data-dependent power calculation methodology using the log likelihood ratio test was successfully used for sample size calculations of mixed pharmacokinetic study designs (i.e. sparsely and densely sampled patients). Such sample size calculations can contribute to a better design of future pharmacokinetic studies. In conclusion, this thesis showed lower exposures for drugs used to treat uncomplicated Plasmodium falciparum malaria during the second and third trimester of pregnancy. More pharmacokinetic studies in pregnant women with a non-pregnant control group are urgently needed to confirm the current findings and to enable an evidence-based dose optimisation. The data-dependent power calculation methodology using the log likelihood ratio test can contribute to an effective design of these future pharmacokinetic studies.

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Wattanatorn, Wiboon. "Pharmacokinetics of 5-fluorouracil in cancer patients." Thesis, Robert Gordon University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389482.

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17

Kingston, Gillian A. "Chiral chromatography of enantiomeric cardiovascular and other drugs." Thesis, University of Surrey, 1990. http://epubs.surrey.ac.uk/844123/.

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Since the enantiomers of a number of racemic drugs have been found to have different activities or modes of action, enantioselective analysis is becoming more important. A number of different approaches to chromatographic chiral resolutions have been evaluated for their ability to resolve the enantiomers of racemic beta blocking drugs, Three chiral HPLC columns were investigated; a cyclodextrin phase, an (R)-3,5-dinitrabezoylphenylglycine phase and a protein phase. The acid glycoprotein phase successfully resolved atenolol, alprenolol, metoprolol, oxprenolol, propranolol and verapamil with 0.01M phosphate buffer eluents modified with either acetonitrile or isopropanol. The (R)-3,5-dinitrobenzoylphenylglycine phase was used with eluents of Isopropanol in hexane and resolutions of propranolol, oxprenolol, metoprolol, alprenolol and pronethalol were achieved after formation of the 1- or 2-naphthamide derivatives, although no separations were achieved for the underivatised samples. The cyclodextrin phase was also found to be unsuccessful in resolving underivatised samples of propranolol and verapamil. However preliminary results indicate that resolutions are possible after the formation of their trifluoroacetyl derivatives. The cyclodextrin phase was also successfully used to resolve the enantiomers of chlorpheniramine and the geometric isomers of clomiphene. In addition to the chiral HPLC stationary phases, a (+)-10-camphorsulphonic acid mobile phase additive was investigated, although this was found to be completely unsuccessful. Finally the use of a chiral diamide GLC column was investigated. This was not suited to the analysis of beta blockers, even after derivatisation, although derivatised amino acids were well resolved. The use of computer modelling to predict the degree of separation of enantlomers was also investigated for the (R)-3,5-dinitrabenzoyl phenylglycine phase, with the interaction energies between the phase and both isomers of each compound calculated for the most stable conformation. From a comparison with the experimental results, it was shown that this approach to prediction was unsuccessful.

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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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McCallion, Orla N. M. "The pharmacokinetics and pharmacodynamics of drugs used to treat asthma." Thesis, Queen's University Belfast, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333800.

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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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21

Carmichael, Samantha Jane. "Optimisation of study design in the pharmacokinetics of anticancer drugs." Thesis, University of Edinburgh, 2001. http://hdl.handle.net/1842/23290.

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"Optimal sampling strategies" are based upon the concept of 'information-rich' times within a concentration-time profile. In this thesis, the selection of optimal sampling times was based on sensitivity analysis and applied to the one and two-compartment PK models. Simulation studies were used to show that parameter estimates obtained using an optimal design method with a reduced number of samples were as good as, if not better than, those obtained from PK studies in which the sampling times were selected empirically. In addition, the effect of adding sampling windows around the "optimal" times offered improved estimation of the inter-subject variability parameters, when compared to designs with fixed sampling times. This result has particular relevance in a clinical setting where a sample may not be collected at the stipulated time, but is still useful in the analysis if the "actual" sampling time is recorded accurately. Further simulations were based on published sampling designs for the anticancer drug carboplatin, and these were used for comparison with the results when an "optimal design" was used. Finally, a population analysis was carried out on data from a phase I clinical trial of the broad-spectrum neuropeptide antagonist, Antagonist G. The parameter values were used to design on "optimal" sampling strategy. As the sample times of the optimal strategy were different to those used in the clinical study, further simulations were used to compare the design. Using sensitivity analysis to design sampling strategies for population PK studies allowed the selection of a minimum number of sampling times, but still resulted in accurate estimation of the parameters of the one and two-compartment PK models. These sampling times provide a basis for PK study design, around which further samples could be added to improve the identification of the model and also the estimation of parameters and their inter and intra-subject of variability.

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Elliott, Christopher T. "Detection, pharmacokinetics and molecular mimicry of beta agonists." Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247342.

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Sood, Pooja. "Assessment of pharmacokinetics and pharmacodynamics of psychoactive drugs using brain microdialysis." Thesis, University of Leicester, 2010. http://hdl.handle.net/2381/8820.

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In order to assess pharmacokinetics and pharmacodynamics (PK/PD) accurately, it is necessary to obtain measurements of the absolute concentrations of compounds in the brain. A major shortcoming of using microdialysis to measure PK/PD is that microdialysis measurements do not give us absolute concentrations of solutes in the brain, since the relationship between dialysate concentrations and true extracellular fluid (ecf) concentrations surrounding the probe is unknown. Several methods have been devised to circumvent this problem. The present study employed a novel method, MetaQuant (MQ) microdialysis, which achieves near 100% recovery, and so enables the measurement of absolute ecf concentrations. I examined the effect of the D4 receptor agonist, PD168077 on extracellular dopamine levels (that is PD) in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of freely moving rats, while simultaneously measuring brain concentrations (that is PK) of the drug. Thus we were able to estimate the PK/PD profile of the drug in the two brain regions. Compared with basal extracellular levels, subcutaneous administration of PD168077 caused significant increase in dopamine in mPFC. Activation of dopamine D4 receptors in the mPFC may improve cognitive function, which is highly impaired in individuals with schizophrenia. Moreover, it has been consistently shown that phencyclidine (PCP) produces robust cognitive disruption, in a novel object recognition (NOR) test. I studied the efficacy of PD168077 to attenuate sub-chronic PCP induced deficit in the NOR task. Sub-chronic PCP induced a robust cognitive disruption and PD168077 (10 mg/kg, s.c. dose) reversed this disruption. Further MQ dialysis data showed that PD168077 (10 mg/kg, s.c. dose) increased dopamine levels in mPFC that was depleted due to PCP suggesting a mechanism for the observed alleviation of PCP induced cognitive deficits.

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Walton, Michael Ian. "The effects of hyperthermia on the pharmacokinetics of selected anticancer drugs." Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.254220.

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Schmitt, Veronika. "Sampling and pharmacokinetics of skin interstitial fluid for therapeutically monitored drugs." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/56176.

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To guide therapeutic decision making, the pharmacokinetics (PK) of certain toxic drugs are typically studied in blood. A drug’s blood concentration is thus acting as a surrogate for its target site concentration. However, a drug’s target is often extravascular and measuring tissue concentrations would be more meaningful. Furthermore, blood sampling is painful and can be challenging for some patients such as children, seriously ill, and old patients; it is, however, currently the standard method for drug testing. Current research suggests that a tissue fluid called interstitial fluid (ISF) can be sampled in minimal amounts without pain and can be used to quantify certain drugs. However, to successfully use this fluid for therapeutic drug monitoring, researchers still face three main challenges: sampling ISF, determining the concentrations and PK of drugs in ISF and their relation to blood concentrations, and quantifying drugs in very small volumes. To improve these challenges, we studied all three areas. First, we reviewed and evaluated methods of extracting ISF. Second, we studied ISF and blood concentrations of 13 drugs in a rabbit model to evaluate their PK. And third, we developed a method for quantifying a drug in just 2 µL of serum from rabbits. Currently available methods need larger sample volumes, whereas ISF is only available in small amounts. We found that many of the drugs we tested in a single-dose study were readily detectable in ISF (vancomycin, gentamicin, methotrexate, cisplatin, carboplatin, valproic acid, phenobarbital, mycophenolic acid and theophylline) and their PK parameters were determined using non-compartmental analysis. Furthermore, steady-state concentrations were predicted from the single-dose study for blood and ISF. At equilibrium, ISF drug concentrations were higher (vancomycin and gentamicin) and more stable compared to blood concentrations. For vancomycin these predictions were confirmed in an additional in vivo study. We further found that the concentration vs. time course of some drugs (vancomycin, gentamicin, methotrexate, valproic acid, phenobarbital, mycophenolic acid, digoxin and theophylline) could be well described by compartmental models. This study shows that ISF can be a valuable matrix for therapeutic drug monitoring and merits further studies to ascertain its clinical utility.
Pharmaceutical Sciences, Faculty of
Graduate

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Abd, Ghani Ramli. "The relationship between the pharmacokinetics of carboplatin and its toxicity." Thesis, University of Brighton, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282926.

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Patel, Chirag G. "The pharmacokinetics and pharmacodynamics of mycophenolic acid in kidney transplant recipients /." View online ; access limited to URI, 2006. http://0-wwwlib.umi.com.helin.uri.edu/dissertations/fullcit/3239911.

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Wang, Jie Stamey James D. "Sample size determination for Emax model, equivalence / non-inferiority test and drug combination in fixed dose trials." Waco, Tex. : Baylor University, 2008. http://hdl.handle.net/2104/5182.

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Mogoa, Eddy Geoffrey Mosoti. "Effects of environmental temperature on pharmacokinetics of, and clinical response to xylazine in goats." Pretoria : [s.n.], 2009. http://upetd.up.ac.za/thesis/available/etd-01052007-110131/.

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Siebert, Gerhard A. "Disposition pharmacokinetics and effects of solutes and drugs in perfused organ systems /." [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18644.pdf.

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Dunagan, Fiona M. "Non-steroidal anti-inflammatory drugs : pharmacokinetics and clinical response in rheumatoid arthritis." Thesis, University of Glasgow, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236497.

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Lilja, Jari. "Effects of grapefruit juice on the pharmacokinetics of selected CYP3A4 substrate drugs." Helsinki : University of Helsinki, 2001. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/lilja/.

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McKellar, Quintin Archibald. "Pharmacokinetics and pharmacodynamics of anti-infective and anti-inflammatory drugs in animals." Thesis, University of Glasgow, 2001. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395088.

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Krishnamoorthy, Mahesh Kumaar. "Effect of Retinal Permeability Variation on Pharmacokinetics of Drugs in the Eye." University of Cincinnati / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1163578450.

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Crabb, Nicholas Clive. "Applications of chiral chromatography to the analysis of drugs and herbicides." Thesis, University of Bradford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.277117.

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Wang, Shining. "DRUG DEVELOPMENT OF TARGETED ANTICANCER DRUGS BASED ON PK/PD INVESTIGATIONS." Diss., Temple University Libraries, 2008. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/2535.

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Pharmaceutics
Ph.D.
EGFR inhibitors, such as gefitinib, are examples of targeted anticancer drugs whose drug sensitivity is related to gene mutations that adds a pharmacogenetic [PG] dimension to any pharmacokinetic [PK] and pharmacodynamic [PD] analysis. The goal of this project was to characterize the PK/PD properties of gefitinib in tumors and then apply these results to design rational drug design regimens, and provide a foundation for future studies with EGFR inhibitors. Progressions of in vitro and in vivo studies were completed to understand the PK and PD behavior of gefitinib. In vitro cytotoxicity assays were first conducted to confirm the gefitinib sensitivity differences in a pair of human glioblastoma cell lines, LN229-wild-type EGFR and LN229-EGFRvIII mutant, an EGFR inhibitor-sensitizing mutation. Subsequent in vitro PD studies identified phosphorylated-ERK1/2 (pERK) as a common PD marker for both cell lines. To describe the most salient features of drug disposition and dynamics in the tumor, groups of mice bearing either subcutaneous LN229-wild-type EGFR or LN229-EGFRvIII mutant tumors were administered gefitinib at doses of 10 mg/kg intravenously (IV), 50 mg/kg intraarterially (IA) and 150 mg/kg orally (PO). In each group, gefitinib plasma and tumor concentrations were quantitated, as were tumoral pERK. Hybrid physiologically-based PK/PD models were developed for each tumor type, which consisted of a forcing function describing the plasma drug concentration-profile, a tumor compartment depicting drug disposition in the tumor, and a mechanistic target-response PD model characterizing pERK in the tumor. Gefitinib showed analogous PK properties in each tumor type, yet different PD characteristics consistent with the EGFR status of the tumors. Using the PK/PD model for each tumor type, simulations were done to define multiple-dose regimens for gefitinib that yielded equivalent PD profiles of pERK in each tumor type. Based on the designed PK/PD equivalent dosing regimens for each tumor type, gefitinib 150 mg/kg PO qd × 15 days and 65 mg/kg PO qd × 15 days multiple-dose studies were conducted in wild-type EGFR and EGFRvIII mutant tumor groups, respectively. In each tumor group, gefitinib plasma and tumor concentrations were measured on both day 1 and day 15, as were tumoral amounts of pERK. Different from single-dose model simulations, gefitinib showed nonlinear PK property in the wild-type tumor due to the down-regulation of membrane transporter ABCG2. Moreover, acquired resistance of tumoral pERK inhibition was observed in both tumor types. Nevertheless, gefitinib had an analogous growth suppression action in both tumor groups, supporting the equivalent PD dosing strategy. Overall, single-dose gefitinib PK/PD investigations in a pair of genetically distinct glioblastomas facilitated the development of hybrid physiologically-based PK/PD models for each tumor type, and further introduced a novel concept of PK/PD equivalent dosing regimens which could be applied in novel drug development paradigms. Preliminary multiple-dose gefitinib studies revealed more complex PK/PD characteristics that needed to be further explored.
Temple University--Theses

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Webb, Hayley Margaret. "Investigation of pharmacokinetics and thioether metabolites to assess bioactivation and toxicity of drugs." Thesis, University of Liverpool, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569256.

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ADRs are a major complication of drug therapy and are one of the main causes of attrition in drug development. Bioactivation of drugs to CRMs is believed to be a crucial step in the development of many direct and immune-mediated ADRs. FS, a furan containing diuretic drug, has been shown to produce massive hepatic necrosis in mice through bioactivation of the furan ring to a reactive epoxide intermediate. A thiophene analogue of FS (TP A) has been synthesized in order to compare the heterocyclic moieties in the same biological environment. NVP, used for the treatment of HIV -1 infection, can cause skin reactions and hepatotoxicity, which are thought to be mediated through CRM formation and subsequent induction of the immune system. FS, TPA and NVP can be used to assess current systems used to investigate the potential hazard of a drug. Substitution of the furan ring in FS to a thiophene ring (TP A) improved the potency towards the pharmacological target; the Na+/2CrlK+ co-transport system in the thick ascending limb of the loop of Henle. It was found that TPA was three times more potent than FS, with ICso values of 17 μM and 50 μM respectively. TPA displayed an improved safety profile in vivo in terms of serum AL T activity levels compared to FS (237.3 and 4441.4 U/L respectively, 1.21 mmol/kg i.p. for 24 hours). Evidence for the bioactivation of TP A, was provided through studies in rat and mouse liver microsomes. Neither FS nor TPA elicited hepatotoxicity or depleted hepatic GSH levels in the rat in vivo. The disposition of FS and TPA were found to be similar in the mouse; however, the plasma AUC increased supraproportionally (~~240-fold to 4300-fold) as the dose was increased from 3/5 to 400 mg/kg orally in the mouse and rat suggesting that, in both species, clearance for both compounds becomes saturated at high oral doses. The toxicokinetic studies reported highlight that the liver exposure in the mouse was twice that in the rat (1.12 mmol/kg i.p.), with free liver AUC values at 243 and 128 ug.h/ml respectively. It was also observed, an i.p. dose of FS induced hepatotoxicity in male mice, yet, at the same dose, orally administered FS failed to do so. Oral administration of FS in the mouse resulted in significantly reduced plasma and liver exposure compared to i.p. administration. NVP was tested in in vitro and in vivo systems for a toxicological end-point; NVP failed to induce cytotoxicity in both male Wistar and female Brown Norway rat hepatocytes, however, a NVP-induced skin rash developed over 3 weeks of daily NVP treatment in female Brown Norway rats. Urinary metabolites were quantified by mass spectrometry on day 7, 14 and 21 of the study; however, no time-dependant trend in any NVP metabolite was observed. No evidence of liver injury or elevation in serum HMGB-l was observed. It is shown, in the work presented, that 12-0H NVP is a substrate for bioactivation; 12-0H NVP was administered to male Wistar rats and only Ml was identified in the bile. Following administration ofNVP to male Wistar rats, both M1 and M2 were identified in the bile. The work presented here has shown that the development of an assessment framework that encompasses all aspects of drug disposition and metabolism, and their relationship with bioactivation and toxicity, would be a valuable tool in drug development. The construction of a decision tree that can be populated with quantitative data could be used in the assessment of NCEs and highlight properties that require optimisation. Outcomes of changes or interventions to a new therapy could then be measured quantitatively and mechanisms defined. A caveat to this framework would stipulate that the model systems employed would have to be carefully selected to best represent the clinical situation. This work highlights the need for improved preclinical hazard assessment and understanding of animal models. Development of more informative and translational biomarkers would allow better clinical hazard identification, as well as improving survivability of NeE during the drug development process.

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38

Potter, Timothy. "Pharmacokinetics and pharmacodynamics of antimicrobial drugs used in the treatment of calf pneumonia." Thesis, Royal Veterinary College (University of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.559067.

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Tong, Xin. "The pharmacokinetics and neuropharmacological action of the new antiepileptic drugs vigabatrin and levetiracetam." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1445126/.

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Epilepsy affects approximately 1% of the world population and is the most serious neurological conditions. In the UK, 30-35,000 new cases of epilepsy are diagnosed each year, resulting in a prevalence of 300,000 nationwide. There is significant need for new drug treatments. Yet we have a poor understanding of how many of these drugs mediate their antiepileptic effect, and how and where they are distributed within the brain. This thesis sought to investigate the pharmacokinetic and neuropharmacokinetic inter-relationship and the neuropharmacology of two new antiepileptic drugs, vigabatrin and levetiracetam two drugs with distinct mechanisms of action. Firstly, a freely moving and freely behaving rat model was used to determine the pharmacokinetics of vigabatrin and levetiracetam simultaneously in serum, cerebrospinal fluid (CSF) and brain frontal cortex and hippocampal extracellular fluid (ECF). Secondly, amino acid neurotransmitter concentrations were monitored in CSF (by direct CSF sampling) and brain ECF (by microdialysis) after vigabatrin and levetiracetam administration. Thirdly, the effects of vigabatrin and levetiracetam on paired-pulse inhibition recorded in the dentate gyrus evoked by perforant path stimulation were established. Vigabatrin rapidly entered the blood (serum), CSF and ECF (frontal cortex and hippocampus) compartments with concentrations increasing linearly and dose- dependently. Time to maximum concentration (rmax) was achieved at a mean value of 0.4 0.06 minutes in the blood compartment, 0.9 0.1 minutes in the CSF compartment and 0.8 0.1 minutes in both the frontal cortex and hippocampal ECF compartments. Although the CSF kinetics of vigabatrin paralleled that seen in serum, CSF vigabatrin concentrations represented only 2% of serum vigabatrin concentrations and did not reflect free drug concentrations in serum. Vigabatrin was not protein bound in serum. Furthermore, the efflux of vigabatrin from the CSF compartment was significantly slower (mean terminal half life {1/2} values, 2.2-3.3 h) than that suggested by serum values (mean tm values, 1.1-1.4 h). Distribution in the brain ECF was brain region specific vigabatrin concentrations achieved in the frontal cortex were 2-fold greater than concentrations achieved in the hippocampus. However, the efflux of vigabatrin from the two brain regions was essentially identical (mean t a values, 2.4-3.6 h) and indeed was similar to values seen in the CSF compartment. The findings are consistent with an active uptake and elimination of vigabatrin from the CSF and ECF. Levetiracetam rapidly entered the blood (serum) and ECF (frontal cortex and hippocampus) compartments with concentrations increasing linearly and dose- dependently. Mean rmax values were 0.4 - 0.7 minutes in the blood compartment and 1.8 - 2.5 minutes in both the frontal cortex and hippocampal ECF compartments. Levetiracetam was not protein bound in serum. In contrast to vigabatrin, levetiracetam did not exhibit brain region specificity in that its neuropharmacokinetic profiles in frontal cortex and hippocampal ECF were essentially identical. However, the efflux of levetiracetam from the two brain regions was slower (mean t a values, 3.1 - 3.3 h) compared to that which occurred in the blood compartment (mean tm values, 2.2 h). In the CSF compartment, vigabatrin administration was associated with changes in 5 of the 16 amino acid neurotransmitter concentrations measured over time. Thus whilst arginine and tyrosine concentrations decreased, homocarnosine, glycine and taurine concentrations increased. Although gamma-aminobutyric acid (GABA) was not measured in CSF, the fact that homocarnosine (a GABA conjugate) concentrations increased is consistent with a GABAergic action for vigabatrin. In the frontal cortex and hippocampal ECF compartments, vigabatrin administration was associated with significant changes in various amino acid concentrations but the changes did not parallel those seen in CSF. The most profound change was that with GABA. However, whilst ECF GABA concentrations increased 6-fold in the frontal cortex, concentrations in the hippocampus were unaffected. These GABA changes did not parallel the concentration versus time profile of ECF vigabatrin nevertheless vigabatrin concentrations in the frontal cortex were 2-fold higher than those achieved in the hippocampus. These findings indicate that CSF amino acid measurements may be a poor reflection of ECF amino acid changes and that changes in ECF amino acids is regionally specific. That vigabatrin reduced paired pulse inhibition in the dentate gyrus evoked by perforant path stimulation at 20 ms interpulse interval but not at 50 ms and 100 ms intervals would suggest that vigabatrin by increasing extracellular GABA may either desensistise synaptic GABAA receptors or inhibit GABA release through an action on GABAB receptors. In the brain ECF compartment, levetiracetam administration was associated with changes in only two (taurine and glutamate) of the 20 amino acid neurotransmitter concentrations measured over time. The significance of these changes in relation to the mechanism of action of levetiracetam is unknown.

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40

Sandall, Joanne Margaret. "A study of factors affecting the pharmacokinetics of drugs in the paediatric population." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.479329.

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41

Landoni, Maria Fabiana. "Pharmacokinetics and pharmacodynamics of non steroidal anti-inflammatory drugs in horses and calves." Thesis, Royal Veterinary College (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281664.

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42

Modzabi, Selorm Kwame Busch Kenneth W. Busch Marianna A. "Studies on new approaches of chiral discrimination for chiral analysis by regression modeling of spectral data." Waco, Tex. : Baylor University, 2009. http://hdl.handle.net/2104/5349.

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Onthank, David C. "Prediction of "First Dose in Human" for radiopharmaceuticals/imaging agents based on allometric scaling of pharmacokinetics in pre-clinical animal models." Link to electronic dissertation, 2005. http://www.wpi.edu/Pubs/ETD/Available/etd-011006-132234/.

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44

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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Calvete, Joanne Amanda. "Pre-clinical studies with the novel colorectal cancer targeted immunotoxin, ICI D0490." Thesis, University of Newcastle Upon Tyne, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336268.

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46

Doroudian, Ahmad. "Pharmacokinetics and conjugative metabolism of labetalol stereoisomers in pregnant sheep : a chiral drug case study in pregnancy." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0022/NQ38879.pdf.

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47

Rimmer, Duncan Adam. "Novel asymmetric microenvironments for separation of enantiomers chiral drugs and natural products." Thesis, Open University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.254965.

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48

Huang, Yi Fei. "Myocardial pharmacokinetics and pharmacodynamics in the sheep /." Title page, contents and abstract only, 1991. http://web4.library.adelaide.edu.au/theses/09PH/09phh8742.pdf.

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Thesis (Ph. D.)--University of Adelaide, Dept. of Anaesthesia and Intensive Care, 1992.
Accompanying diskette contains data of Chapters 3, 4, 5, 7, 8 and 9 (ASCII). Includes bibliographical references (leaves 177-207).

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49

Zhang, Yuan. "The role of drug disposition genes for variability in the pharmacokinetics of antiretroviral drugs." Thesis, University of Liverpool, 2013. http://livrepository.liverpool.ac.uk/9075/.

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The failure of highly active antiretroviral therapy may be due to pharmacological factors such as drug transporters and metabolism enzymes. Drug transporters and metabolism enzymes played complementary roles in drug absorption, distribution, metabolism and excretion by biotransformation and counter-transport, particularly in the intestine while nuclear receptors as transcription factors regulate the expression of drug transporters and metabolism enzymes. In this thesis, a positive correlation between nuclear receptors expression and the expression of ABC transporters and OATP transporters in intestine were observed while a negative correlation was found between the gene expression of nuclear receptors and cytochrome P450 enzymes in intestine. Single nucleotide polymorphisms in genes could potentially impact on gene expression of drug transporters and metabolism enzymes. The polymorphisms of nuclear receptors were associated with the expression of ABC transporters. Drug concentrations have a high inter-individual variability in patients receiving the same dose of antiretroviral drugs, which could affect outcome of antiretroviral therapy. There are many factors that may affect plasma concentrations such as age, gender, body weight, ethnicity, genetic factors and so on. In a Ghanaian cohort, a negative correlation was found between the body weight and the EFV plasma concentration. Genetic factors such as the polymorphisms of cytochrome P450 enzymes also influenced efavirenz plasma concentrations. Meanwhile, efavirenz plasma concentrations were associated with the viral load in plasma within a UK cohort. Nanomedicine involves new and promising technologies that may enable and improve the targeted delivery of antiretroviral drugs. The permeability of lopinavir in the Caco-2 cell line was improved by formulation of nanodispersions. However, the permeability of efavirenz was decreased for all nanodispersions in MDCKII and MDCKII-ABCB5 cell lines. Comparing efficiency of efavirenz nanodispersions transcellular permeability in MDCKII and MDCKII-ABCB5 cell lines indicated that ABCB5 is able to transport efavirenz when incubated as dissolved molecule or nanodispersion. It is support by the copy number variation of ABCB5 had no relationship with EFV plasma concentrations. In summary, this thesis has attempted to determine the pharmacological factors influencing pharmacokinetics of HIV drugs, including drug transporters, metabolism enzymes and nuclear receptors. Data illustrating the factors that influence efavirenz plasma concentrations which are important for viral suppression were also generated. Furthermore, the nanodispersion technology is worthy of further study in order to improve drug delivery and drug distribution of antiretroviral drugs.

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Friberg, Lena E. "Pharmacokinetic-Pharmacodynamic Modelling of Anticancer Drugs : Haematological Toxicity and Tumour Response in Hollow Fibres." Doctoral thesis, Uppsala University, Division of Pharmacokinetics and Drug Therapy, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3370.

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Established quantitative relationships between dose, plasma concentrations and response [pharmacokinetic-pharmacodynamic (PKPD) models] have a high potential in improving therapeutic indices of anticancer drug therapy and in increasing drug development efficiency. PKPD modelling is a helpful tool for characterising and understanding schedule dependence. The aim of this thesis was to develop PKPD models of anticancer drugs for tumour effects and haematological toxicity, which is the most frequent dose-limiting toxicity.

PK and haematological toxicity after several schedules were studied in rats and semi-physiological PKPD models for the whole time course of myelosuppression were developed from animal and patient data. The possibility to implant hollow fibres filled with tumour cells in immunocompetent rats was investigated for simultaneous assessment of PK, tumour response and haematological toxicity. Population data analyses were performed using the software NONMEM.

When all injections were administered within eight hours, fractionated schedules of 5-fluorouracil and epirubicin produced similar haematological toxicity in rats as a single dose, when the non-linear PK of 5-fluorouracil was accounted for. When the time interval was extended to two days for 5-fluorouracil, the fractionated regimens were more toxic.

The developed semi-physiological PKPD models included transit compartments that mimic maturation stages in bone marrow and explain the time lag. Feedback mechanisms characterised the rebound. The models successfully described myelosuppression in patients (DMDC) and rats (5-fluorouracil), after different administration schedules. Further developments made it possible to characterise the time course of myelosuppression after administration of each one of six different drugs, with parameters related to the haematopoietic system consistent across drugs.

The developed hollow fibre model in immunocompetent rats was successfully applied to monitor PK, toxicity and the time course of antitumour effects. PKPD modelling illustrated that the schedule dependence of the anticancer agent CHS 828 is partly due to dose-dependent bioavailability and partly due to a schedule-dependent PD effect.

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Dissertations / Theses on the topic 'Pharmacokinetics. Drugs Chiral drugs'

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