Electronic Theses and Dissertations

Date of Award

2012

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

Department

Pharmaceutics and Drug Delivery

First Advisor

Bonnie A. Avery

Second Advisor

Christopher R. Mccurdy

Third Advisor

Seongbong Jo

Relational Format

dissertation/thesis

Abstract

Cocaine and opioid abuse are a major public health concern and the cause of significant morbidity and mortality worldwide. The development of effective medication for cocaine and opioid abuse is necessary to reduce the impact of this issue upon the individual and society. The pharmacologic treatment for drug abuse has been based on one of the following strategies: agonist substitution, antagonist treatment, or symptomatic treatment. This dissertation is focused on the role of metabolism and pharmacokinetics in the development of new pharmacotherapies, CM304 (sigma-1 receptor antagonist), mitragynine and 7-hydroxymitragynine (μ-opioid receptor agonists), for the treatment of drug abuse. The affinity of cocaine to sigma-1 receptors render the hypothesis that targeting sigma-1 receptors using antagonists will be an effective strategy in the development of novel medications for cocaine abuse. In this light, we screened several sigma-1 receptor antagonists using in vitro metabolism studies and selected CM304, (3-(2-(azepan-1-yl) ethyl)-6-(3-fluoropropyl) benzo[d]thiazol-2(3H)-one), as a lead compound. CM304 was further characterized by determining its physicochemical properties such as pKa, Log PO/W and Log DPBS, pH 7.4, solubility, protein binding, in vitro metabolic stability. We also investigated pharmacokinetic parameters and bioavailability of CM304 in rats using a validated UPLC-MS/MS method. Mitragyna speciosa Korth is a tropical plant indigenous to Southeast Asia. The leaves of the plant have been used as a traditional medicine to treat cough, fever, diarrhea, pain, hypertension and morphine addicts. Mitragynine and 7-hydroxymitragyne, corynanthine-like alkaloids, have been reported to be responsible for the opioid properties found in this plant. We have developed simple, sensitive and high throughput bioanalytical methods for the quantification of mitragynine and 7-hydroxymitragyne in rat plasma. Pharmacokinetic parameters were evaluated by conducting single dose in vivo pharmacokinetic studies in rats. The extent of brain penetration of 7-hydroxymitragyne in rats was determined by performing an in vivo brain to plasma ratio. The above in vitro and in vivo experiments discussed on this dissertation will lay the groundwork for further development of these compounds as pharmacotherapies for cocaine and opioid abuse.

Concentration/Emphasis

Emphasis: Pharmaceutics

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