Di-(3-²H₃-propyl)acetic acid was synthesized and used in pharmacokinetic and metabolism studies of dipropyl acetic acid (valproic acid). Kinetic equivalence of valproic acid and valproic acid-²Hg₆ was demonstrated in a single dose study in a human volunteer. An isotope effect was observed for w-oxidation but the difference in metabolism of the two isotopic forms was not sufficient to make valproic acid-²Hg₆ biologically nonequivalent. In a multiple dose study, the kinetics of valproic acid-²Hg₆ were determined in the presence of steady state concentrations of valproic acid in the same volunteer. Concentrations of valproic acid and valproic acid-²Hg₆ in serum and saliva were determined by gas chromatography mass spectrometry using selected ion monitoring. Saliva drug levels were measured with good precision down to 0.1 μg/ml. Compared to single dose kinetic data, the total body clearance of valproic acid-²Hg₆ increased by 33% at steady state. This could be explained by an increase in the serum free drug fraction. At steady state, intrinsic clearance was found to decrease. Good correlation was found between concentrations of valproic acid in saliva and serum. Serum and urinary metabolites were characterized as their methyl, trimethylsilyl or tert-butyldimethylsilyl derivatives. The metabolism study was facilitated by using the stable isotope tracer technique. A diunsaturated metabolite was identified in serum and urine. The presence of a molecular ion doublet in the mass spectrum reduces the possible structures for this metabolite. A new metabolite, 2-propyl-4-keto-pentanoic acid, was detected in serum and urine and 2-propylsuccinic acid and 2-propylmalonic acid were characterized as metabolites. The identification of metabolites was also verified using synthesized reference compounds. / Pharmaceutical Sciences, Faculty of / Graduate

Folic acid is present in foods in many different forms. Concentrations of N⁵-methyltetrahydrofolic acid (one form of folate) were determined by a radioassay and the Lactobacillus casei microbiological assay methods. The coefficient of determination for samples analyzed by both methods was 0.86 but the radioassay method was found to be faster, simpler and more accurate than the microbiological method. The milk folate binder and L. casei were found to react differently to pteroylglutamic acid (another form of folate) compared to N⁵-methyltetrahydrofolic acid. The two methods of assay were found to be suitable only for measuring the form of folate used to construct the standard curve for the assay. It was found that neither method could be used to quantify- folate levels in foods accurately. Thus, at best, presently available data on food folate levels can only be compared to other values obtained by an identical method. Also folate concentration values presently available may not necessarily be a reflection of their nutritional significance to man. The radioassay method was used for the measurement of N⁵-methyltetrahydrofolic acid degradation under various conditions. It was found that N⁵-methyltetrahydrofolic acid degradation in the presence of an unlimited oxygen supply could be described as a pseudo first order reaction. Rate constants for the reaction were found to increase as the temperature of the reaction increased and were described in terms of the Arrhenius equation. The overall reaction appeared to be second order in the presence of a limited oxygen supply. The presence of mercaptoethanol in the assay system delayed the beginning of the N⁵-methyltetrahydrofolic acid degradation reaction. The presence of ascorbic acid in the N⁵-methyltetrahydrofolic acid/buffer solution also delayed the start of the reaction. The reaction rate constants were not altered by the presence of the two reducing agents, however. The degradation of N⁵-methyltetrahydrofolic acid was therefore concluded to be an oxidation reaction. The degradation product was identified as N⁵-methyldihydrofolic acid by ultraviolet spectroscopy. The results of this research implicate the importance of reducing agents in foods containing folate which are subjected to heat processing. Experiments with food materials containing ascorbic acid and exposed to high temperatures indicated that the degradation of free folate was delayed by the presence of the reducing agent. / Land and Food Systems, Faculty of / Graduate

The porphyrias are a group of disorders characterized by the excessive excretion of haem precursors in urine and stool. in the past two decades, isotopic studies led to impressive progress in our understanding of both normal and disordered porphyrin metabolism but despite these advanaces, many aspects of latter are still unexplained.

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Thesis (M.S.)--Mississippi State University. Department of Chemical Engineering. / Title from title screen. Includes bibliographical references.

Thesis (Ph. D.)--University of Nebraska--Lincoln, 1999. / PDF text: [2] leaves abstract, vii, 105 leaves : ill. Includes bibliographical references (leaves 103-105 of dissertation).