Tissue concentrations of clozapine and its metabolites in the rat.
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.
Baldessarini
R J
RJ
Consolidated Department of Psychiatry and Neuroscience Program, Harvard Medical School, McLean Hospital, Belmont, MA 02178.
Centorrino
F
F
Flood
J G
JG
Volpicelli
S A
SA
Huston-Lyons
D
D
Cohen
B M
BM
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D005473:Fluoxetine / Q000494:pharmacology; D006207:Half-Life; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000494:pharmacology
D005473:Fluoxetine; C058272:norclozapine; D014635:Valproic Acid; D003024:Clozapine