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Pharmacokinetics and pharmacodynamics of protein turnover and production in vivo

Kim, Jonghan

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2004, Doctor of Philosophy, Ohio State University, Pharmacy.
The overall objective of this dissertation was quantitative characterization of the pharmacokinetics of the proteins albumin and vitellogenin, with a focus on their biosynthesis. Albumin was studied for the possible role of the receptor FcRn, the major histocompatibility complex-related Fc receptor, in its biosynthesis. Vitellogenin biosynthesis was studied as an example of receptor-dependent protein production controlled by a complex hormonal signaling system. Albumin was quantified in biological matrices using sodium dodecylsulfate-polyacrylamide gel electrophoresis and immunoprecipitation for separation and enzyme-linked immunosorbent assay for quantification. The analytical methods were validated by high degrees of purity (~100%) and linearity (R2 > 0.999). Using FcRn-deficient knock-out (KO) mice and radioiodinated albumin as a tracer, FcRn was recently shown to protect albumin from degradation, also indicating indirectly lower albumin production rate in KO compared with control mice. To further explore the role of FcRn in albumin production, the albumin production rate in WT and KO mice was measured using a kinetic analysis of the plasma appearance of tritiated albumin after intravenous bolus injection of tritiated leucine. An increase in albumin production rate (~20%) in KO compared with WT mice contradicted the indirect evidence based upon iodinated albumin, suggesting that radioiodinated albumin failed to mimic the behavior of endogenous albumin, possibly due to structural changes induced by the iodination and/or purification procedures. Vitellogenin (Vg), an egg-yolk precursor protein, is synthesized in the fish liver, transported to the ovaries, and incorporated into developing oocytes. The estrogen-receptor complex up-regulates Vg production by binding to its recognition element on nuclear DNA, stimulating mRNA and Vg production. Receptor-mediated up-regulation of Vg biosynthesis was incorporated into a pharmacokinetic/pharmacodynamic model that accurately predicted the plasma concentration of Vg in male rainbow trout after continuous water exposure to the synthetic estrogen 17-a-ethynylestradiol. Estrogen levels are under control of pituitary-derived gonadotropins which in turn are controlled by hypothalamus-derived gonadotropin releasing hormone after appropriate environmental cues. A biologically-based, mathematical model was developed and integrated the biology of hormone signaling and feedback systems which included key intermediate steps; e.g., sex steroid synthesis, gonadotropin gene induction and peptide synthesis with their control of oocyte maturation and spawning.
William Hayton (Advisor)

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Citations

  • Kim, J. (2004). Pharmacokinetics and pharmacodynamics of protein turnover and production in vivo [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1100554543

    APA Style (7th edition)

  • Kim, Jonghan. Pharmacokinetics and pharmacodynamics of protein turnover and production in vivo. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1100554543.

    MLA Style (8th edition)

  • Kim, Jonghan. "Pharmacokinetics and pharmacodynamics of protein turnover and production in vivo." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1100554543

    Chicago Manual of Style (17th edition)