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Pharmaceutical Impact of the Different Ionization States of a Weakly Basic Drug within a Living Organism
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Pharmaceutical Impact of the Different Ionization States of a Weakly Basic Drug within a Living Organism. |
| 개인저자 | Murashov, Mikhail D. |
| 단체저자명 | University of Michigan. Pharmaceutical Sciences. |
| 발행사항 | [S.l.]: University of Michigan., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 256 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-04B. Dissertation Abstract International |
| ISBN | 9781687927422 |
| 학위논문주기 | Thesis (Ph.D.)--University of Michigan, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
Advisor: Rosania, Gustavo. |
| 이용제한사항 | This item must not be sold to any third party vendors.This item must not be added to any third party search indexes. |
| 요약 | Clofazimine (CFZ), an oral FDA-approved antibiotic for over 40 years, has been used effectively against leprosy and multi-drug resistant tuberculosis (MDR-TB). Due to its atypical pharmacokinetic parameters, orally administered CFZ free base is associated with extensive intracellular bioaccumulation of the solid drug, primarily in tissue macrophages, in a form of crystal-like drug inclusions (CLDIs) that chemically and structurally resemble CFZ hydrochloride salt (CFZ-HCl) crystals. These biocrystals are biocompatible, stable, long-lived, relatively non-toxic, and have anti-inflammatory properties.In this dissertation, I hypothesized that CFZ-HCl is a more therapeutically efficacious form of CFZ compared to CFZ free base that could be potentially used in the repurposing CFZ for other indications. To test this hypothesis, first, I established the physicochemical parameters of CFZ (e.g. pHmax, apparent pKa, CFZ-HCl aqueous solubility, CFZ free base intrinsic solubility, Ksp, etc.) that allowed me to understand the different ionization states of CFZ and their relationship to the drug's physicochemical, pharmacokinetic, and pharmacodynamic properties. In fact, these physicochemical parameters explained the thermodynamic mechanism of differential stabilization and accumulation of the HCl salt form of CFZ in macrophage lysosomes. Based on this mechanism, I developed a specific buffer system that mimics the macrophage intralysosomal microenvironment, which ultimately helped me to determine that CFZ free base is associated with the major side effect from CFZ treatment, drug-induced skin pigmentation, that results from its partitioning into subcutaneous fat layer of the skin.Next, I developed a biomimetic formulation of CFZ drug biocrystals, micronized CFZ-HCl salt crystals, and investigated its stability in macrophages in vitro and in vivo. As a result, I determined that macrophages internalize and stabilize CFZ-HCl microcrystals, just as well as CLDIs, without any detectable toxicological effects. Furthermore, no skin pigmentation was observed when an equivalent total amount of CFZ-HCl to the total oral dose that causes maximal skin pigmentation was administered. Thus, parenteral biomimetic formulations of CFZ-HCl could be instrumental in avoiding the pigmentation side effect of oral CFZ therapy.Finally, I explored the inflammatory status and efficacy of my formulation of CFZ-HCl salt microcrystals in gouty arthritis under local administration in vivo, utilizing an FDA-recognized rat model. As a result, local injection of CFZ-HCl microcrystals led to the recruitment of macrophages to the site of action, a pro-inflammatory response, and did not facilitate the dissolution and clearance of monosodium urate (MSU) crystals from the joint, the main source of inflammation, by lowering the local pH of the synovium. Even though the results of this study suggested that my formulation is not suitable for gouty arthritis, further investigation is required to determine efficacy and anti-inflammatory action of my formulation in MDR-TB and other potential new indications.Overall, this dissertation augments the understanding of drug distribution and mechanism of action by effectively demonstrating how it is possible to distinguish the differential contribution of different ionization states of a drug (e.g. CFZ) to the drug's efficacy and toxicity properties. Furthermore, this dissertation has advanced the rational design of formulations, in terms of being the first to develop a biomimetic form of a small molecule drug and demonstrating how the role of macrophages in determining the stability of biomimetic formulations can be probed. |
| 일반주제명 | Pharmaceutical sciences. |
| 언어 | 영어 |
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