Tissue concentrations of clozapine and its metabolites in the rat

Neuropsychopharmacology. 1993 Sep;9(2):117-24. doi: 10.1038/npp.1993.50.


Clozapine (CLZ) and its metabolites norclozapine (NOR) and clozapine-N-oxide (NOX) were assayed in rat serum and brain tissue after intraperitoneal injection of CLZ. Clozapine levels rose with dose, averaging 28 ng/ml (87 nmol/L) serum per milligram/kilogram dose. Brain- and serum-CLZ levels correlated closely, averaging 24-fold higher in brain. Norclozapine and NOX averaged approximately 58% and 13% of CLZ in serum, respectively, whereas in brain, NOR was detected only at doses greater than or equal to 10 mg/kg (approximately 5.6% of CLZ) and NOX was undetectable. Levels peaked within 30 minutes, and elimination of CLZ from brain and CLZ or NOR from blood was very rapid (half-life = 1.5 to 1.6 hours). A week of daily dosing with CLZ led to no accumulation of drug in brain; a week of fluoxetine pretreatment increased analyte concentrations (serum, 86%; brain, 61%), but valproate had little effect.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Clozapine / analogs & derivatives
  • Clozapine / blood
  • Clozapine / metabolism
  • Clozapine / pharmacokinetics*
  • Fluoxetine / pharmacology
  • Half-Life
  • Male
  • Mass Spectrometry
  • Rats
  • Rats, Sprague-Dawley
  • Valproic Acid / pharmacology


  • Fluoxetine
  • norclozapine
  • Valproic Acid
  • Clozapine