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 A. Grant, Verginia C. Cuzon Carlson

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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
Issue number2
StatePublished - Feb 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


Dive into the research topics of 'A comparative study of the pharmacokinetics of clozapine N-oxide and clozapine N-oxide hydrochloride salt in rhesus macaques'. Together they form a unique fingerprint.

Cite this