TY - JOUR T1 - A comparative study of the pharmacokinetics of clozapine N-oxide and clozapine N-oxide hydrochloride salt in rhesus macaques JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.252031 SP - jpet.118.252031 AU - Daicia C Allen AU - Timothy L Carlson AU - Yan Xiong AU - Jian Jin AU - Kathleen A Grant AU - Verginia C Cuzon Carlson Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/12/06/jpet.118.252031.abstract N2 - Translating chemogenetic techniques from non-human 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 FDA boxed warnings. Additionally, the limited solubility of CNO requires high concentrations of potentially toxic detergents such as dimethyl sulfoxide (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 min 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 6-7 fold higher plasma concentrations of CNO as that of CNO-DMSO, and relatively less clozapine (3-5% clozapine/CNO in CNO-DMSO group and 0.5-1.5% clozapine/CNO in CNO-HCl group). Both groups had large between subjects variability, pointing to the necessity to perform individual CNO pharmacokinetic studies prior to further experimentation. The ratio of CNO measured in the CSF was between 2-6% 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 to 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. ER -