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J Pharmacol Exp Ther. 2019 Feb;368(2):199-207. doi: 10.1124/jpet.118.252031. Epub 2018 Dec 6.

A Comparative Study of the Pharmacokinetics of Clozapine N-Oxide and Clozapine N-Oxide Hydrochloride Salt in Rhesus Macaques.

Author information

1
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon (D.C.A., K.A.G., V.C.C.C.); Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon (T.L.C., K.A.G., V.C.C.C.); and Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (Y.X., J.J.).
2
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon (D.C.A., K.A.G., V.C.C.C.); Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon (T.L.C., K.A.G., V.C.C.C.); and Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (Y.X., J.J.) cuzoncar@ohsu.edu.

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.

PMID:
30523062
PMCID:
PMC6337003
[Available on 2020-02-01]
DOI:
10.1124/jpet.118.252031

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