PMID- 28324647
OWN - NLM
STAT- MEDLINE
DCOM- 20180130
LR  - 20181202
IS  - 1948-7193 (Electronic)
IS  - 1948-7193 (Linking)
VI  - 8
IP  - 7
DP  - 2017 Jul 19
TI  - Metabolism and Distribution of Clozapine-N-oxide: Implications for Nonhuman 
      Primate Chemogenetics.
PG  - 1570-1576
LID - 10.1021/acschemneuro.7b00079 [doi]
AB  - 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.
FAU - Raper, Jessica
AU  - Raper J
AUID- ORCID: 0000-0002-0964-9944
AD  - Yerkes National Primate Research Center , Atlanta, Georgia 30329, United States.
FAU - Morrison, Ryan D
AU  - Morrison RD
AD  - Sano Informed Prescribing, Inc. Franklin, Tennessee 37067, United States.
FAU - Daniels, J Scott
AU  - Daniels JS
AD  - Sano Informed Prescribing, Inc. Franklin, Tennessee 37067, United States.
FAU - Howell, Leonard
AU  - Howell L
AD  - Yerkes National Primate Research Center , Atlanta, Georgia 30329, United States.
AD  - Department of Psychiatry and Behavioral Sciences, School of Medicine, Emory 
      University , Atlanta, Georgia 30322, United States.
FAU - Bachevalier, Jocelyne
AU  - Bachevalier J
AD  - Yerkes National Primate Research Center , Atlanta, Georgia 30329, United States.
AD  - Department of Psychology, Emory University , Atlanta, Georgia 30322, United 
      States.
FAU - Wichmann, Thomas
AU  - Wichmann T
AD  - Yerkes National Primate Research Center , Atlanta, Georgia 30329, United States.
AD  - Department of Neurology, School of Medicine, Emory University , Atlanta, Georgia 
      30322, United States.
AD  - Udall Center of Excellence for Parkinson's Disease Research, Emory University , 
      Atlanta, Georgia 30329, United States.
FAU - Galvan, Adriana
AU  - Galvan A
AUID- ORCID: 0000-0001-9939-0130
AD  - Yerkes National Primate Research Center , Atlanta, Georgia 30329, United States.
AD  - Department of Neurology, School of Medicine, Emory University , Atlanta, Georgia 
      30322, United States.
AD  - Udall Center of Excellence for Parkinson's Disease Research, Emory University , 
      Atlanta, Georgia 30329, United States.
LA  - eng
GR  - P50 NS098685/NS/NINDS NIH HHS/United States
GR  - P51 OD011132/OD/NIH HHS/United States
PT  - Journal Article
DEP - 20170330
PL  - United States
TA  - ACS Chem Neurosci
JT  - ACS chemical neuroscience
JID - 101525337
RN  - 0 (ABCG2 protein, human)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Neoplasm Proteins)
RN  - J60AR2IKIC (Clozapine)
RN  - MZA8BK588J (clozapine N-oxide)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & 
      inhibitors/genetics/metabolism
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & 
      inhibitors/genetics/metabolism
MH  - Animals
MH  - Antipsychotic Agents/blood/cerebrospinal fluid/*pharmacokinetics
MH  - Blood-Brain Barrier/drug effects/metabolism
MH  - Capillary Permeability/drug effects
MH  - Clozapine/*analogs & derivatives/blood/cerebrospinal fluid/pharmacokinetics
MH  - Dogs
MH  - Dose-Response Relationship, Drug
MH  - Drug Evaluation, Preclinical
MH  - Female
MH  - Humans
MH  - Macaca mulatta
MH  - Madin Darby Canine Kidney Cells
MH  - Male
MH  - Neoplasm Proteins/antagonists & inhibitors/genetics/metabolism
MH  - Transfection
PMC - PMC5522181
MID - NIHMS875092
OTO - NOTNLM
OT  - DREADDs
OT  - Rhesus macaque
OT  - blood-brain barrier
OT  - clozapine
OT  - pharmacokinetics
COIS- Notes The authors declare no competing financial interest.
EDAT- 2017/03/23 06:00
MHDA- 2018/01/31 06:00
PMCR- 2018/07/19
CRDT- 2017/03/22 06:00
PHST- 2017/03/23 06:00 [pubmed]
PHST- 2018/01/31 06:00 [medline]
PHST- 2017/03/22 06:00 [entrez]
PHST- 2018/07/19 00:00 [pmc-release]
AID - 10.1021/acschemneuro.7b00079 [doi]
PST - ppublish
SO  - ACS Chem Neurosci. 2017 Jul 19;8(7):1570-1576. doi: 10.1021/acschemneuro.7b00079. 
      Epub 2017 Mar 30.