Multiscale Biodistribution Analysis of Lipophilic, Poorly Soluble Drugs.
dc.contributor.author | Baik, Jason | en_US |
dc.date.accessioned | 2012-06-15T17:29:57Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2012-06-15T17:29:57Z | |
dc.date.issued | 2012 | en_US |
dc.date.submitted | en_US | |
dc.identifier.uri | https://hdl.handle.net/2027.42/91404 | |
dc.description.abstract | Clofazimine is a poorly soluble drug that accumulates as solid deposits in the body during prolonged oral administration. At the outset, we hypothesized that clofazimine accumulated intracellularly by a passive and spontaneous crystallization, and in various levels of experimental set-ups, from a tissue culture to mouse models. We found that clofazimine readily formed amorphous inclusions in complexes with intracellular membranes in MDCK cells, while different types of inclusions were found in the tissue macrophages of clofazimine-diet fed mice. Most of the inclusions in vivo appeared as vibrant red, birefringent, 10 – 20 µm length crystal-like structures; however, their physicochemical and morphological characteristics were inconsistent with those of pure clofazimine crystals. Most remarkably, among the inclusions from macrophages, we discovered a new cytoplasmic structure delimited by double membranes with internal supramolecular organizations resembling stacks of lipidic lamellae. Upon prolonged dosing, the intact clofazimine was redistributed from adipose tissues to the lymphatic organs paralleled by anti-inflammatory responses such as splenomegaly, liver microgranulomas, and an expansion of macrophage populations. In conclusion, instead of passive intracellular crystallization hypothesis, I propose that clofazimine accumulates in vivo by active sequestration in the immune system. By constructing intracellular crystal- and organelle-like “polyhedrosomes”, the macrophages can impact the clofazimine’s systemic pharmacokinetics and biodistribution, from micro to macro scale. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | Drug Inclusion Formation in Cells, Tissues, and Bodies | en_US |
dc.subject | Clofazimine Bioaccumulation and Pharmacokinetics | en_US |
dc.subject | Polyhedrosome Formation in Macrophages | en_US |
dc.subject | EM Study of Clofazimine | en_US |
dc.title | Multiscale Biodistribution Analysis of Lipophilic, Poorly Soluble Drugs. | 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 | Burant, Charles | en_US |
dc.contributor.committeemember | Rodriguez-Hornedo, Nair | en_US |
dc.contributor.committeemember | Smith, David E. | en_US |
dc.subject.hlbsecondlevel | Pharmacy and Pharmacology | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/91404/1/jsbaik_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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