A comparative study of the pharmacokinetics of clozapine N-oxide and clozapine N-oxide hydrochloride salt in rhesus macaques

Daicia C. Allen, Timothy L. Carlson, Yan Xiong, Jian Jin, Kathleen (Kathy) Grant, Verginia Cuzon Carlson

    Research output: Contribution to journalArticle

    Abstract

    Translating chemogenetic techniques from nonhuman primates to potential clinical applications has been complicated in part due to in vivo conversion of the chemogenetic actuator, clozapine N-oxide (CNO), to its pharmacologically active parent compound, clozapine, a ligand with known side effects, including five boxed warnings from the Food and Drug Administration. Additionally, the limited solubility of CNO requires high concentrations of potentially toxic detergents such as dimethylsulfoxide (DMSO). To address these concerns, pharmacokinetic profiling of commercially available CNO in DMSO (CNO-DMSO, 10% v/v DMSO in saline) and a water-soluble salt preparation (CNO-HCl, saline) was conducted in rhesus macaques. A time course of blood plasma and cerebrospinal fluid (CSF) concentrations of CNO and clozapine was conducted (30–240 minutes post-administration) following a range of doses (3–10 mg/kg, i.m. and/or i.v.) of CNO-DMSO or CNO-HCl. CNO-HCl resulted in 6- to 7-fold higher plasma concentrations of CNO compared to CNO-DMSO, and relatively less clozapine (3%–5% clozapine/CNO in the CNO-DMSO group and 0.5%–1.5% clozapine/CNO in the CNO-HCl group). Both groups had large between-subjects variability, pointing to the necessity of performing individual CNO pharmacokinetic studies prior to further experimentation. The ratio of CNO measured in the CSF was between 2% and 6% of that measured in the plasma and did not differ across drug preparation, indicating that CSF concentrations may be approximated from plasma samples. In conclusion, CNO-HCl demonstrated improved bioavailability compared with CNO-DMSO with less conversion to clozapine. Further investigation is needed to determine if brain concentrations of clozapine following CNO-HCl administration are pharmacologically active at off-target monoaminergic receptor systems in the primate brain.

    Original languageEnglish (US)
    Pages (from-to)199-207
    Number of pages9
    JournalJournal of Pharmacology and Experimental Therapeutics
    Volume368
    Issue number2
    DOIs
    StatePublished - Feb 1 2019

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    Macaca mulatta
    Pharmacokinetics
    Salts
    Dimethyl Sulfoxide
    Clozapine
    clozapine N-oxide
    Cerebrospinal Fluid
    Primates
    Drug Labeling
    Drug Compounding
    Poisons
    Brain
    United States Food and Drug Administration

    ASJC Scopus subject areas

    • Molecular Medicine
    • Pharmacology

    Cite this

    A comparative study of the pharmacokinetics of clozapine N-oxide and clozapine N-oxide hydrochloride salt in rhesus macaques. / Allen, Daicia C.; Carlson, Timothy L.; Xiong, Yan; Jin, Jian; Grant, Kathleen (Kathy); Cuzon Carlson, Verginia.

    In: Journal of Pharmacology and Experimental Therapeutics, Vol. 368, No. 2, 01.02.2019, p. 199-207.

    Research output: Contribution to journalArticle

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    abstract = "Translating chemogenetic techniques from nonhuman primates to potential clinical applications has been complicated in part due to in vivo conversion of the chemogenetic actuator, clozapine N-oxide (CNO), to its pharmacologically active parent compound, clozapine, a ligand with known side effects, including five boxed warnings from the Food and Drug Administration. Additionally, the limited solubility of CNO requires high concentrations of potentially toxic detergents such as dimethylsulfoxide (DMSO). To address these concerns, pharmacokinetic profiling of commercially available CNO in DMSO (CNO-DMSO, 10{\%} v/v DMSO in saline) and a water-soluble salt preparation (CNO-HCl, saline) was conducted in rhesus macaques. A time course of blood plasma and cerebrospinal fluid (CSF) concentrations of CNO and clozapine was conducted (30–240 minutes post-administration) following a range of doses (3–10 mg/kg, i.m. and/or i.v.) of CNO-DMSO or CNO-HCl. CNO-HCl resulted in 6- to 7-fold higher plasma concentrations of CNO compared to CNO-DMSO, and relatively less clozapine (3{\%}–5{\%} clozapine/CNO in the CNO-DMSO group and 0.5{\%}–1.5{\%} clozapine/CNO in the CNO-HCl group). Both groups had large between-subjects variability, pointing to the necessity of performing individual CNO pharmacokinetic studies prior to further experimentation. The ratio of CNO measured in the CSF was between 2{\%} and 6{\%} of that measured in the plasma and did not differ across drug preparation, indicating that CSF concentrations may be approximated from plasma samples. In conclusion, CNO-HCl demonstrated improved bioavailability compared with CNO-DMSO with less conversion to clozapine. Further investigation is needed to determine if brain concentrations of clozapine following CNO-HCl administration are pharmacologically active at off-target monoaminergic receptor systems in the primate brain.",
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