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Metabolism and Distribution of Clozapine-N-oxide: Implications for Nonhuman Primate Chemogenetics
- Publication Year :
- 2017
-
Abstract
- The use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in neuroscience has rapidly expanded in rodent studies but has lagged behind in nonhuman primate (NHP) experiments, slowing the development of this method for therapeutic use in humans. One reason for the slow adoption of DREADD technology in primates is that the pharmacokinetic properties and bioavailability of clozapine-n-oxide (CNO), the most commonly used ligand for human muscarinic (hM) DREADDs, are not fully described in primates. We report an extensive pharmacokinetic study using subcutaneous (SC) administration of CNO in five adult rhesus monkeys. CNO reached maximal plasma and cerebrospinal fluid (CSF) concentrations within 2 h after injection, with an observed dose-dependent increase in levels following a 3 and 10 mg/kg SC dose. Since CSF concentrations were below values predicted from unbound plasma concentrations, we investigated whether CNO was restricted from the CNS through active transport at the blood-brain barrier. In vitro assessment demonstrated that CNO is a substrate for P-glycoprotein (Pgp; efflux ratio, 20), thus providing a likely mechanism limiting CNO levels in the CNS. Furthermore, CNO is metabolized to the psychoactive compounds clozapine and n-desmethylclozapine in monkeys. The concentrations of clozapine detected in the CSF are sufficient to activate several types of receptor (including the hM-DREADDs). Our results suggest that CNO metabolism and distribution may interfere with reproducibility and interpretation of DREADD-related experiments in NHPs and calls for a re-evaluation of the use of CNO in DREADD-related experiments in NHPs along with the need to test alternative compounds.
- Subjects :
- 0301 basic medicine
Male
Physiology
Cognitive Neuroscience
Drug Evaluation, Preclinical
Pharmacology
Blood–brain barrier
Transfection
Biochemistry
Article
Madin Darby Canine Kidney Cells
Capillary Permeability
03 medical and health sciences
0302 clinical medicine
Dogs
Pharmacokinetics
Muscarinic acetylcholine receptor
medicine
Distribution (pharmacology)
ATP Binding Cassette Transporter, Subfamily G, Member 2
Animals
Humans
ATP Binding Cassette Transporter, Subfamily B, Member 1
Receptor
Clozapine
biology
Dose-Response Relationship, Drug
Cell Biology
General Medicine
Chemogenetics
biology.organism_classification
Macaca mulatta
Bioavailability
Neoplasm Proteins
Rhesus macaque
030104 developmental biology
medicine.anatomical_structure
Blood-Brain Barrier
Female
030217 neurology & neurosurgery
Antipsychotic Agents
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....d1255835261b2e587f4e1e832cd3f759