Abstract
Efforts to find a correlation between serum levels of chlorpromazine (CPZ) and clinical effect have been rather unsuccessful, which could be due to fluctuations of CPZ and CPZ metabolite levels during treatment, the complicated metabolism of CPZ, or to varying degrees of protein binding. Using a mass fragmentographic analysis technique the variations of CPZ and two active metabolites nor1-CPZ and 7-OH-CPZ were studied in ten schizophrenic patients during the day at steady state and after withdrawal.
There was a significant correlation between the area under curve (AUC) for CPZ in serum during 24-h treatment and serum concentration at different fixed times of the day. The half-life (T 1/2) for CPZ was found to be 8–33h. 7-OH-CPZ and nor1-CPZ disappeared at about the same rate as the parent compound. The concentration of both metabolites was less than 10 ng/ml after 36 h.
CPZ was administered to 43 schizophrenic patients in one of three fixed doses (200, 400, or 600 mg) according to a double-blind design. Plasma and cerebrospinal fluid (CSF) samples were analysed before and after both 2 and 4 weeks' treatment. The levels of the metabolites were considerably lower as compared to CPZ levels. The same levels were found after 2 and 4 weeks' treatment. There were no sex differences.
The levels of CPZ and metabolites presented a weak positive correlation to daily dose but not to dose calculated by mg/kg body weight. Older patients tended to have higher CPZ and metabolite levels. The dose effects were very similar in plasma and CSF and there was a highly significant correlation between CPZ levels in serum and CSF. CSF/plasma ratio for CPZ seems to be an individual factor possibly related to variations in protein-binding in plasma and CSF.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alfredsson G, Wode-Helgodt B, Sedvall G (1976) A mass fragmentographic method for the determination of chlorpromazine and two of its active metabolites in human plasma and CSF. Psychopharmacology 48:123–131
Alfredsson G, Sedvall G, Wiesel F-A, Wode-Helgodt B (1980) The relevance of measuring chlorpromazine in serum In: Usdin E, Eckert H, Forrest I (eds) Phenothiazines and structurally related drugs, 4th International Symposium on Phenothiazines and Related Drugs, p 199
Axelsson R, Mårtensson E (1976) Serum concentration and elimination from serum of thioridazine in psychiatric patients. Curr Ther Res 19:242–265
Creese I, Manian AA, Prosser TD, Snyder SH (1978) 3H-haloperidol binding to dopamine receptors in rat corpus striatum: Influence of chlorpromazine metabolites and derivatives. Eur J Pharmacol 47: 291–296
Curry SH (1976) Metabolism and kinetics of chlorpromazine in relation to effect. In: Sedvall G, Uvnäs B, Zotterman Y (eds) Antipsychotic drugs: pharmacodynamics and pharmacokinetics. Pergamon Press, Oxford, pp 343–352
Curry SH (1978) Antipsychotic drugs I. Chlorpromazine: Pharmacokinetics, plasma levels and clinical response. In: Burrows GD, Norman T (eds) Plasma levels of psychotropic drugs and clinical response. Marcel Dekker, New York Basel
Dahl SG, Strandfjord RE (1977) Pharmacokinetics of chlorpromazine after single and chronic dosage. Clin. Pharmacol Ther 21:437–448
Ferguson GA (1966) Statistical analysis in psychology and education. 2nd ed. McGraw-Hill, New York
Freedberg KA, Innis RB, Creese I, Snyder SH (1979) Antischizophrenic drugs: Differential plasma protein binding and therapeutic activity. Life Sci 24:2467–2474
Mackay AVP, Healey AF, Baker J (1974) The relationship of plasma chlorpromazine to its 7-hydroxy and sulphoxide metabolites in a large population of chronic schizophrenics. Brit J Clin Pharmacol 1:425–430
Miller RJ, Iversen LL (1974) Effect of chlorpromazine and some of its metabolites on the dopamine-sensitive adenylate cyclase of rat brain striatum. Comm J Pharm Pharmacol 26:142–144
Nybäck H, Sedvall G (1972) Effect of chlorpromazine and some of its metabolites on synthesis and turnover of catecholamines formed from 14C-tyroxine in mouse brain. Psychopharmacologia (Berl) 26:155–160
Overall J, Klett EJ (1972) Applied multivariate analysis. McGraw-Hill, New York
Phillipson OT, McKeown JM, Baker J, Healey AF (1977) Correlation between plasma chlorpromazine and its metabolites and clinical ratings in patients with acute relapse of schizophrenic and paranoid psychosis. Brit J Psychiat 131:172–184
Piafsky KM, Borgå O, Odar-Cederlöf I, Johansson C, Sjöqvist F (1978) Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma acid glycoprotein. New Engl J Med 299:1435–1439
Potter WZ, Bertilsson L, Sjöqvist F (1980) Clinical pharmacokinetics of psychotropic drugs — fundamental and practical aspects. In: van Praag HM (ed) Handbook of Biological Psychiatry, Vol 4, Section 3 (in press)
Rivera-Calimlim L, Castaneda L, Lasagna L (1973) Effects of mode of management on plasma chlorpromazine in psychiatric patients. Clin Pharmacol Ther 14:978–985
Rivera-Calimlim L, Nasrallah H, Strauss J, Lasagna L (1976) Clinical response and plasma levels: Effect of dose, dosage schedules, and drug interactions on plasma chlorpromazine levels. Am J Psychiatry 133:646–652
Rivera-Calimlim L, Gift T, Nasrallah HA, Wyatt RJ, Lasagna L (1978) Correlation between plasma concentrations of chlorpromazine and clinical response. Comm Psychopharmacol 2:215–222
Sakalis G, Stephen HC, Mould GP, Lader H (1972) Physiologic and clinical effects of chlorpromazine and their relationship to plasma level. Clin Pharmacol Ther 13:931–945
Sakalis G, Chan TL, Gershon S, Park S (1973) The possible role of metabolites in therapeutic response to chlorpromazine treatment. Psychopharmacologia (Berl) 32:279–284
Sakalis G, Chap TL, Sathananthan G, Schooler N, Goldberg S, Gershon S (1977) Relationships among clinical response, extra-pyramidal syndrome and plasma chlorpromazine and metabolite ratios. Comm Psychopharmacol 1:157–166
Sakurai Y, Nakahara T, Takahashi R (1975) Prediction of response to chlorpromazine treatment in schizophrenics. Psychopharmacologia (Berl) 44:195–203
Snedecor GW, Cochran WG (1967) Statistical methods. Iowa State University Press, Ames, Iowa
Wode-Helgodt B, Sedvall G (1978) Correlations between height of subject and concentrations of monoamine metabolites in cerebrospinal fluid from psychotic men and women. Comm Psychopharmacol 2:177–183
Wode-Helgodt B, Fyrö B, Gullberg B, Sedvall G (1977a) Effect of chlorpromazine treatment on monoamine metabolites levels in cerebrospinal fluid of psychotic patients. Acta Psychiat Scand 56:129–142
Wode-Helgodt B, Eneroth P, Fyrö B, Gullberg B, Sedvall G (1977b) The effect of chlorpromazine treatment on prolactin levels in cerebrospinal fluid and plasma of psychotic patients. Acta Psychiat Scand 56:280–293
Wode-Helgodt B, Borg A, Fyrö B, Sedvall G (1978) Clinical effects and drug concentrations in plasma and cerebrospinal fluid in psychotic patients treated with fixed doses of chlorpromazine. Acta Psychiat Scand 58:149–173
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wode-Helgodt, B., Alfredsson, G. Concentrations of chlorpromazine and two of its active metabolites in plasma and cerebrospinal fluid of psychotic patients treated with fixed drug doses. Psychopharmacology 73, 55–62 (1981). https://doi.org/10.1007/BF00431102
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00431102