Dehalogenation and N-dealkylation of chlorpromazine as revealed by plasma concentrations of metabolites in a population of chronically medicated schizophrenics.
Dehalogenaton and N-demethylation of chlorpromazine (CPZ) were studied in twelve psychotic inpatients orally treated for four weeks with a daily CPZ dose of 6.4 +/- 1.1 (S.E.) mg/kg body weight (1.5-14.1, range). Weekly drug and metabolite plasma concentrations were measured by a gas liquid chromatography-nitrogen/phosphorus detector method (GLC/NPD). Plasma concentrations of the parent compound CPZ, of the dehalogenated metabolite promazine (PZ) and of the N-dealkylated metabolites N-monodemethylated chlorpromazine (CPZ-nor1) and N-didemethylated chlorpromazine (CPZ-nor2) had already reached a steady state by the end of the first week of treatment. During the entire treatment period the major plasma component was found to be PZ. Patients (N = 6) on a low dose regimen (3.7 +/- 0.2 mg/kg body weight) showed significantly lower mean plasma concentrations of CPZ and nor metabolites than patients (N = 6) on a higher dose regimen (8.6 +/- 0.7 mg/kg body weight). PZ mean plasma concentrations, however, were not significantly different in the two groups of patients, indicating that the yield of the CPZ dechlorination pathway, as opposed to that of the N-demethylation pathway, was already maximal at the CPZ concentrations attained under the low dose regimen. Male patients (N = 5) exhibited significantly higher mean PZ plasma concentrations over the 4 week period of the study than female patients (N = 7).
Valoti
M
M
Centro Interdipartimentale di Ricerca sul Metabolismo dei Farmaci Psicotropi, Università di Siena, Italy.
Palmi
M
M
Della Corte
L
L
Nardini
M
M
Corti
P
P
Sgaragli
G P
GP
D000328:Adult; D002746:Chlorpromazine / Q000097:blood* / Q000627:therapeutic use; D002849:Chromatography, Gas; D003640:Dealkylation; D005260:Female; D006219:Halogens / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D012044:Regression Analysis; D012559:Schizophrenia / Q000097:blood* / Q000188:drug therapy
D006219:Halogens; D002746:Chlorpromazine