The fate of bacterial cocaine esterase (CocE): An in vivo study of CocE-mediated cocaine hydrolysis, CocE pharmacokinetics, and CocE elimination

Remy L. Brim, Kathleen R. Noon, Gregory T. Collins, Aron Stein, Joseph Nichols, Diwa Narasimhan, Mei Chuan Ko, James H. Woods, Roger K. Sunahara

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Cocaine abuse and toxicity remain widespread problems in the United States. Currently cocaine toxicity is treated only symptomatically, because there is no Food and Drug Administrationapproved pharmacotherapy for this indication. To address the unmet need, a stabilized mutant of bacterial cocaine esterase [T172R/G173Q-CocE (DM-CocE)], which hydrolyzes cocaine into inactive metabolites and has low immunogenic potential, has been developed and previously tested in animal models of cocaine toxicity. Here, we document the rapid cocaine hydrolysis by low doses of DM-CocE in vitro and in vivo, as well as the pharmacokinetics and distribution of the DM-CocE protein in rats. DM-CocE at 50.5 μg/kg effectively eliminated 4 mg/kg cocaine within 2 min in both male and female rats as measured by mass spectrometry. We expanded on these findings by using a pharmacologically relevant dose of DM-CocE (0.32 mg/kg) in rats and monkeys to hydrolyze convulsant doses of cocaine. DM-CocE reduced cocaine to below detection limits rapidly after injection; however, elimination of DM-CocE resulted in peripheral cocaine redistribution by 30 to 60 min. Elimination of DM-CocE was quantified by using [ 35S] labeling of the enzyme and was found to have a half-life of 2.1 h in rats. Minor urinary output of DM-CocE was also observed. Immunohistochemistry, Western blotting, and radiography all were used to elucidate the mechanism of DM-CocE elimination, rapid proteolysis, and recycling of amino acids into all tissues. This rapid elimination of DM-CocE is a desirable property of a therapeutic for cocaine toxicity and should reduce the likelihood of immunogenic or adverse reactions as DM-CocE moves toward clinical use.

Original languageEnglish (US)
Pages (from-to)83-95
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume340
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'The fate of bacterial cocaine esterase (CocE): An in vivo study of CocE-mediated cocaine hydrolysis, CocE pharmacokinetics, and CocE elimination'. Together they form a unique fingerprint.

Cite this