Author ORCID Identifier
Date Available
5-9-2025
Year of Publication
2023
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Pharmacy
Department/School/Program
Pharmaceutical Sciences
First Advisor
Chang-Guo Zhan
Second Advisor
Charles Loftin
Abstract
Cocaine is a widely abused, hepatotoxic drug without an FDA-approved pharmacotherapy specific for cocaine addiction or overdose. Cocaine-induced toxicity in animals and humans is due to its multiple physiological effects on the central nervous system, cardiovascular system, etc. The toxicity of cocaine is highly complex, as its metabolites also contribute to the toxicity. Notably, the combination of cocaine and alcohol is common among drug users and can produce additional metabolites. Some of the metabolites are more toxic than cocaine itself. Hence, to develop an ideal therapeutic candidate, the candidate should not only account for cocaine but should also detoxify other active metabolites. It is recognized as a promising therapeutic strategy to accelerate cocaine metabolism which can convert cocaine to pharmacologically inactive metabolite(s) using an efficient cocaine-metabolizing enzyme. Our previous studies have successfully designed and discovered a highly efficient cocaine hydrolase, denoted as CocH5-Fc(M6), capable of rapidly hydrolyzing cocaine at the benzoyl ester moiety. This dissertation is aimed to obtain a complete in vitro/vivo profile of CocH5-Fc(M6) in pre-clinical treatment of cocaine use disorders for guiding future clinical studies. Firstly, how does a non-lethal dose of alcohol affect the metabolism and toxicity of cocaine was studied. The cardiotoxicity and blood toxicity level were also examined for cocaine and its metabolites. Secondly, the activity of CocH5-Fc(M6) against cocaine and its active metabolites in vitro and the effectiveness of a CocH5-Fc(M6) for cocaine toxicity treatment were evaluated. In the last chapter of the studies, the in vitro and in vivo stability of CocH5-Fc(M6) was evaluated and the pharmacokinetic/pharmacodynamic profiles of CocH5-Fc(M6) were developed to predict the effects of CocH5-Fc(M6) for cocaine addiction treatment. In conclusion, all the toxicity data have consistently demonstrated that co-administration of alcohol makes cocaine more toxic, and that the alcohol-enhanced toxicity of cocaine is mainly attributed to the observed two additional metabolites, cocaethylene and norcocaethylene. CocH5-Fc(M6) can rapidly and completely convert cocaine and its active metabolites to inactive metabolites with a relatively longer half-life. The clinical potential to treat cocaine overdose and addiction was manifested.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2023.213
Recommended Citation
Shang, Linyue, "Effectiveness of a long-acting cocaine hydrolase in metabolizing cocaine and its physiologically active metabolites" (2023). Theses and Dissertations--Pharmacy. 144.
https://uknowledge.uky.edu/pharmacy_etds/144
