Pharmacokinetic and pharmacodynamic studies of chlorpromazine in rats: effect of chlorpromazine on dopamine and dopamine metabolite concentration in rat striatum.
The concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum were increased after the i.v. administration of chlorpromazine (CPZ). Assuming that the enhancement of dopamine concentration in the striatum after CPZ administration is caused by the release of dopamine from the dopamine neuronal terminals, the relationship between the enhancement of dopamine concentration in the striatum and CPZ concentration in the cerebrospinal fluid (CSF) and the striatum were analyzed using the sigmoid Emax model. The enhancement of dopamine concentration in the striatum could be described quantitatively by this model. The time courses of DOPAC and HVA concentration in the striatum after CPZ administration were analyzed using the dopamine metabolism model, which has an apparent first-order clearance from dopamine to DOPAC and HVA, and also using the Michaelis-Menten type elimination kinetics of DOPAC and HVA. The values of the metabolism parameters for DOPAC and HVA were fixed to the estimated values of the L-dopa study. The calculated values of DOPAC and HVA concentrations in the striatum were greater than those of the observed data. The elimination parameters for DOPAC and HVA were reestimated by the nonlinear least squares method. The time courses of DOPAC and HVA concentration in the striatum could be described using these reestimated elimination parameters. These results indicated that the turnover rate of dopamine and dopamine metabolites, DOPAC and HVA in the striatum after CPZ administration is different from that after L-dopa administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Sato
S
S
Department of Pharmaceutics, Niigata College of Pharmacy, Japan.
Koitabashi
T
T
Koshiro
A
A
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002746:Chlorpromazine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D016018:Least-Squares Analysis; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D018492:Dopamine Antagonists; D015102:3,4-Dihydroxyphenylacetic Acid; D002746:Chlorpromazine; D004298:Dopamine; D006719:Homovanillic Acid