Introduction of new immunosuppressive drugs has transformed liver transplantation from an experimental procedure to a successful solution for patients who are otherwise doomed to death. However, the use of these drugs has resulted in significant morbidity and mortality due to their toxicity. Recent data indicates that local immunosuppression at the site of transplanted graft will increase graft survival and reduce the toxicity of immunosuppressive agents in other organs. However, current methods of local immunosuppression have several limitations, which seriously hamper their clinical use. We propose here to use macromolecular prodrugs of immunosuppressants, which preferentially accumulate in the liver, for the purpose of local immunosuppression in liver transplantation. Specifically, we will investigate the tissue accumulation and immunosuppressive profile of a dextran prodrug of methylprednisolone (MP) in rats. Our hypothesis is that the dextran prodrug of MP will preferentially accumulate in the liver, where it gradually regenerates the active drug, resulting in sustained local immunosuppression in liver transplantation. Prodrugs will be synthesized by attaching dextran to MP via various linkers, and an optimum linker will be selected. The pharmacokinetics of the selected prodrug will then be tested in rats with respect to the dose and frequency of prodrug administration. Further, the effects of the prodrug on the systemic and local immune response will be compared with those of the parent drug. Finally, the effectiveness of the prodrug in prevention of allograft rejection will be compared with those of the parent drug in an orthotopic rat liver transplantation model. It is our expectation that this approach will substantially reduce the drug dose needed for effective immunosuppression of transplanted livers in rats. These studies are significant because they will eventually lead to a substantial reduction in morbidity and mortality associated with the current immunosuppressive protocols used in liver transplantation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Okita, Richard T
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Texas Tech University
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Schools of Pharmacy
United States
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Shaik, Imam H; Agarwal, Hitesh K; Parang, Keykavous et al. (2012) Hepatic immunosuppressive effects of systemically administered novel dextran-methylprednisolone prodrugs with peptide linkers in rats. J Pharm Sci 101:4003-12
Penugonda, Suman; Agarwal, Hitesh K; Parang, Keykavous et al. (2010) Plasma pharmacokinetics and tissue disposition of novel dextran-methylprednisolone conjugates with peptide linkers in rats. J Pharm Sci 99:1626-37
Zhang, Shuang-Qing; Thorsheim, Helen R; Penugonda, Suman et al. (2009) Liquid chromatography-tandem mass spectrometry for the determination of methylprednisolone in rat plasma and liver after intravenous administration of its liver-targeted dextran prodrug. J Chromatogr B Analyt Technol Biomed Life Sci 877:927-32
Penugonda, Suman; Kumar, Anil; Agarwal, Hitesh K et al. (2008) Synthesis and in vitro characterization of novel dextran-methylprednisolone conjugates with peptide linkers: effects of linker length on hydrolytic and enzymatic release of methylprednisolone and its peptidyl intermediates. J Pharm Sci 97:2649-64
Chimalakonda, Anjaneya P; Mehvar, Reza (2007) Effects of methylprednisolone and its liver-targeted dextran prodrug on ischemia-reperfusion injury in a rat liver transplantation model. Pharm Res 24:2231-8
Chimalakonda, Anjaneya P; Montgomery, Donald L; Weidanz, Jon A et al. (2006) Attenuation of acute rejection in a rat liver transplantation model by a liver-targeted dextran prodrug of methylprednisolone. Transplantation 81:678-85
Shaik, Imam H; Mehvar, Reza (2006) Rapid determination of reduced and oxidized glutathione levels using a new thiol-masking reagent and the enzymatic recycling method: application to the rat liver and bile samples. Anal Bioanal Chem 385:105-13