Cheminformatic and Mechanistic Study of Drug Subcellular Transport/Distribution.
dc.contributor.author | Zheng, Nan | en_US |
dc.date.accessioned | 2012-01-26T19:59:56Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2012-01-26T19:59:56Z | |
dc.date.issued | 2011 | en_US |
dc.date.submitted | 2011 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/89626 | |
dc.description.abstract | The subcellular transport and distribution behavior determines both the pharmacological effect on the cellular level and the drug exposure at a tissue, organ and whole body level. Despite of the rapid evolution in experimental and computational approaches for studying the subcellular transport of small molecules, a thorough understanding and reliable experimental analysis of cellular pharmacokinetic behavior remain challenging. Mechanism-based computational models are promising tools for testing hypothesis, exploring mechanism and guiding experiment design and data analysis in pharmacokinetic and system biology studies. The primary goal of this work is to propose a hypothesis-driven, simulation-guided strategy for drug subcellular transport and distribution studies. The current knowledge of organelle targeting features of small molecules was analyzed in terms of its relevance to developing computational models for analyzing subcellular pharmacokinetic behavior. A non-invasive insert system was designed to characterize small molecules’ intercellular transport kinetics, and a mechanism-based passive diffusion model was adapted to facilitate the design and analysis of subcellular distribution and intercellular transport experiments. This study pointed out many opportunities to advance effective screening for drug candidates with desirable distribution and transport behavior at a subcellular and systemic level. These opportunities include: 1) the development of quantitative experimental platform for the real-time tracking and analysis of non-fluorescent molecules in multiple subcellular compartments; 2) the elaboration of hypothesis-driven, mechanistic modeling techniques emphasizing a better understanding of the non-steady-state intracellular accumulation behavior and limited intercellular diffusivity; 3) the promotion of simulation-guided experimental design strategy; and 4) the incorporation of synthetic biology concepts into pharmacokinetics studies. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | Pharmacokinetics | en_US |
dc.subject | Subcellular Transport | en_US |
dc.subject | Organelle-targeting | en_US |
dc.subject | Drug Delivery | en_US |
dc.subject | Modeling and Simulation | en_US |
dc.title | Cheminformatic and Mechanistic Study of Drug Subcellular Transport/Distribution. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Pharmaceutical Sciences | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Rosania, Gustavo | en_US |
dc.contributor.committeemember | Amidon, Gordon L. | en_US |
dc.contributor.committeemember | Feng, Meihua Rose | en_US |
dc.contributor.committeemember | Shedden, Kerby A. | en_US |
dc.subject.hlbsecondlevel | Pharmacy and Pharmacology | en_US |
dc.subject.hlbsecondlevel | Science (General) | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/89626/1/nanzh_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.