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Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 70-75).

Although many commercial chemicals can dissociate, the study of the biological and environmental fate of ionogenic organic chemicals (IOCs) is still in its infancy. Uptake of the veterinary drug diclofenac in vultures and cattle was successfully simulated with a newly developed physiologically-based pharmacokinetic model for IOCs, lending credence to diclofenac’s proposed role in South Asian vulture population declines. Proteins and phospholipids rather than total lipids control the tissue distribution of diclofenac. A method was developed to simultaneously extract neutral and acidic pesticides and benzotriazoles from water samples with recoveries ranging 70-100%. This method was applied to samples from a laboratory calibration experiment of the Polar Organic Chemical Integrative Sampler. The sampler had higher uptake for neutral and acidic pesticides when filled with triphasic sorbent admixture and OASIS MAS sorbent, respectively. While either sorbent can also be applied for methylated benzotriazoles, neither is capable of quantitatively sampling all three compound groups.

Vegetation plays an important role in the partitioning, transport and fate of hydrophobic organic contaminants (HOCs) in the environment. This thesis aimed at addressing two key knowledge gaps in our understanding of how plants exchange HOCs with the atmosphere: (1) To improve our understanding of the uptake of HOCs into, and transfer through, leaves of different plant species which can significantly influence the transport and fate of HOCs in the environment; and (2) To evaluate an experimental approach to measure fluxes of HOCs in the field. The methods presented in papers I, II and III contribute to increasing our understanding of the fate and transport of HOCs in leaves by offering straightforward ways of measuring mass transfer coefficients through leaves and partition ratios of HOCs between leaves, leaf lipids and lipid standards and reference materials like water, air and olive oil. The passive dosing study in paper III in particular investigated the role of the composition of the organic matter extracted from leaves in determining the capacity of the leaves to hold chemicals and found no large differences between 7 different plant species, even though literature data on leaf/air partition ratios (Kleaf/air) varies over 1-3 orders of magnitude. In paper IV we demonstrated that the modified Bowen ratio method can be extended to measure fluxes of persistent organic pollutants (POPs) if the fluxes do not change direction over the course of the sampling period and are large enough to be measured. This approach thus makes it possible to measure fluxes of POPs that usually require sampling times of days to weeks to exceed method detection limits. The experimental methods described in this thesis have the potential to support improved parameterization of multimedia models, which can then be evaluated against fluxes measured in the field using the modified Bowen ratio approach. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.</p>

In recent years there has been a great deal of scientific interest in processes that affect the fate of organic chemicals in the environment. one main reason for this increased interest is due to greater environmental concern over accidental or purposeful release of these chemicals into the environment by man. A major environmental concern is the increased use of pesticides over the last few years. In the thirty years prior to 1978 the use of pesticides has increased by a factor of forty (Ridgeway et al., 1978). Recently the use of herbicides has been increasing, but that of insecticides has stabilized (Willis, 1983). Detectable amounts of organic pesticides can be found in many areas of the biosphere. For toxic organic chemicals to be used safely, researchers must have a clear understanding of the fate and persistence of these chemicals when they are released into the environment. This understanding will also allow the development of new products that, when properly used, will not produce adverse effects to man or the environment (Weber, 1972). According to the Toxic Substance Control Act (TSCA) any new or expanded-use chemical that might be released into the environment must be tested for environmental hazard.

Although many commercial chemicals can dissociate, the study of the biological and environmental fate of ionogenic organic chemicals (IOCs) is still in its infancy. Uptake of the veterinary drug diclofenac in vultures and cattle was successfully simulated with a newly developed physiologically-based pharmacokinetic model for IOCs, lending credence to diclofenac’s proposed role in South Asian vulture population declines. Proteins and phospholipids rather than total lipids control the tissue distribution of diclofenac. A method was developed to simultaneously extract neutral and acidic pesticides and benzotriazoles from water samples with recoveries ranging 70-100%. This method was applied to samples from a laboratory calibration experiment of the Polar Organic Chemical Integrative Sampler. The sampler had higher uptake for neutral and acidic pesticides when filled with triphasic sorbent admixture and OASIS MAS sorbent, respectively. While either sorbent can also be applied for methylated benzotriazoles, neither is capable of quantitatively sampling all three compound groups.

Diss. (sammanfattning) Umeå : Univ., 2006. / Härtill 5 uppsatser.

The present study was divided between two different drug delivery goals, each involving naltrexone (NTX) or its active metabolite, 6-β-naltrexol (NTXOL). First, amino acid esters of NTX and NTXOL were prepared in order to test their candidacy for microneedle-enhanced transdermal delivery. Second, a 3-O-(-)-cytisine-naltrexone (CYT-NTX) codrug was prepared for screening as a potential oral delivery form of NTX and (-)-cytisine (CYT). The amino acid prodrugs were intended for the treatment of alcohol abuse, while the codrug was designed as a single agent for the treatment of alcoholism and tobacco-dependency co-morbidities. One hypothesis of this work was that prodrugs of NTX or NTXOL can be designed that possess superior skin transport properties through microneedle-treated skin compared to parent NTX or NTXOL. Nine amino acid ester prodrugs were prepared, and only three 6-O amino acid ester prodrugs of NTXOL were stable enough at skin pH (pH 5.0) to move forward to studies in 50% human plasma. 6-O-β-Ala-NTXOL, the lead compound, exhibited the most rapid bioconversion to NTXOL in human plasma (t1/2 = 2.2 ± 0.1 h); however, this in vitro stability value indicates that the prodrug may require hepatic enzyme-mediated hydrolysis for sufficiently rapid bioconversion to NTXOL in vivo. A second hypothesis of this work was that a CYT-NTX codrug could be designed with appropriate stability characteristics for oral delivery. CYT-NTX was found to be stable over the time course of 24 h in buffer systems of pH 1.5, 5.0, 7.4 and 9.0, and in 80% rat plasma, 80% human plasma, simulated gastric fluid and simulated intestinal fluid. Six (3 rats/group) Sprague-Dawley male rats were dosed i.v. with 1 mg/kg CYT-NTX codrug, or 10 mg/kg, p.o. Oral administration of a 10 mg/kg dose of CYT-NTX codrug resulted in rapid absorption and distribution (5 min) of CYT-NTX codrug, and NTX was released from codrug with a peak plasma concentration of 6.8 ± 0.9 nmol/L reached within 65 minutes. Plasma CYT was not detected; however, NTX delivery was achieved with a fraction absorbed value of 13%. Thus, CYT-NTX may hold promise as a potential oral codrug for further optimization and development.

In enzymatic and synthetic catalytic oxidations, high-valent iron-oxo intermediates play a vital role as the active oxidant. In this regard, many synthetic metal catalysts are designed as biomimetic models to resemble the active site of Cytochrome P450 enzymes (P450) which are the predominant oxidation catalysts in nature. Vitamin B12 cofactors, with a corrole-like structure corrin, are also utilized in some of the more difficult reactions in nature such as rearrangement and reductase reactions. In this work, application of the promising photochemical method to corrolecontaining ligands systems showed much success in the generation of manganese(V)-oxo corrole intermediates using two electron-deficient corrole ligands 5,10,15-tris-(4- trifluoromethylphenyl) corrole (4-CF3)TPC and 5,10,15-tris-(4-nitrophenyl) corrole (4- NO2)TPC. Homolytic cleavage of the O-N or O-ClO2 bond led to generation of the detectable manganese(V)-oxo corroles which were found to act as a competent oxotransfer agent in the presence of various organic reductants. The reaction was marked by the return to a low-valent manganese(III) corrole through a direct oxygen atom transfer (OAT) pathway or formation of manganese(VI)-oxo corrole and manganese(IV) product through a disproportionation pathway. The photo-generated manganese(V)-oxo corrole intermediates were tested as the oxidizing agent for substrate oxidation reactions. More importantly, accomplished within this work is the synthesis for a novel porphyrin complex with light-harvesting functionalities. The light harvesting porphyrin complex (L-Por) exhibits remarkable spectral absorption properties within the range of 400-550 nm allowing for the efficient harvesting of a broad spectrum of light. It is expected that the attached antennae chromophores and metalloporphyrin core will absorb visible light and, at the same time, the antennae could transfer energy to the metalloporphyrin core. Ruthenium(II)(L-Por)(CO) was found to efficiently photo-eject the carbonyl ligand when subjected to visible light. Generation of ruthenium(VI)(LPor)( O)2 was achieved through application of sacrificial oxidant iodobenzene diacetate (PhI(OAc)2). Stoichiometric oxidation of ruthenium(VI)(L-Por)(O)2 formed ruthenium(IV)(L-Por)(O) and cis-cyclooctene oxide with observed rate constants that were 10-fold greater under visible light irradiation. Future investigations will employ a bis-porphyrin-diruthenium(IV)-μ-oxo dimeric complex as a potential catalyst in photocatalytic aerobic oxidation reactions.