The presence of 7-hydroxychlorpromazine in CSF of chlorpromazine-treated patients

Alfredsson, Gunnel; Lindberg, Monica; Sedvall, Göran

doi:10.1007/bf00432774

Cited by 13 publications

(11 citation statements)

References 12 publications

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“…Different antipsychotic drugs and drug metabolites may, however, have different 44 blood-brain distribution ratios because of differences in protein binding in both plasma and CSF (Alfredsson et al 1982(Alfredsson et al , 1984aNyberg et al 1981;Wode-Helgodt & Alfredsson 1981). The dopamine receptor-blocking activity in plasma of psychiatric patients may, therefore, not be directly correlated to neuroleptic-induced dopamine receptor-blocking activity in the brain.…”

Section: Influence Of Blood-brain Distribution On Results Using Radiomentioning

confidence: 91%

“…7-Hydroxy chlorpromazine also has an antipsychotic effect when administered directly to patients (Kleinman et al 1980), and it reaches cerebrospinal fluid (CSF) concentrations in the same range as that of the parent drug, chlorpromazine, after oral administration (Alfredsson et al 1982). However, no significant contribution from 7-hydroxy chlorpromazine and N-monodesmethyl chlorpromazine to therapeutic response could be found in a study by Wode-Helgodt et al (1978).…”

Section: Thioridazine and Chlorpromazinementioning

confidence: 94%

“…On the other hand, metabolites of chlorpromazine, formed by the same pathways, usually attain lower plasma levels than chlorpromazine itself (Alfredsson et al 1982;Curry 1981). …”

Section: Active Metabolites 0/ Antipsychotic Drugsmentioning

confidence: 98%

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Plasma Level Monitoring of Antipsychotic Drugs Clinical Utility

Dahl

1986

Clinical Pharmacokinetics

145

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The steady-state plasma concentrations of antipsychotic drugs show large interpatient variations but remain relatively stable from day to day in each individual patient. Monitoring of antipsychotic drug concentrations in plasma might be of value provided the patients are treated with only 1 antipsychotic drug. Some studies have reported a relationship between therapeutic response and serum antipsychotic drug 'concentrations' as measured using the radioreceptor assay (RRA) method, which measures dopamine receptor-blocking activity in plasma. Most studies, however, have failed to demonstrate such a relationship, and the RRA does not seem to provide the generally useful tool for plasma concentration monitoring of antipsychotic drugs that was hoped for initially. A lack of correlation between dopamine receptor-blocking activity in plasma and therapeutic response may be due to differences in the blood-brain distribution of both antipsychotic drugs and their active metabolites. Chemical assay methods (e.g. GLC and HPLC) have been used in studies which examined the relationships between therapeutic response and antipsychotic drug concentrations in red blood cells and in plasma. It seems that for these drugs, measuring red blood cell concentrations does not offer any significant advantage over measuring plasma concentrations. Reasonably controlled studies of plasma concentration-response relationships using randomly allocated, fixed dosages of chlorpromazine, fluphenazine, haloperidol, perphenazine, sulpiride, thioridazine and thiothixene have been published but often involve relatively few patients. A correlation between therapeutic response and plasma concentrations of thioridazine and its metabolites has not been demonstrated, and plasma level monitoring of thioridazine and its metabolites therefore appears to have no clinical value. Clinical behavioural deterioration concomitant with high plasma concentrations of chlorpromazine and haloperidol have been reported. A dosage reduction might be considered after 2 to 4 weeks' treatment in non-responders who have plasma chlorpromazine concentrations above 100 to 150 micrograms/L or plasma haloperidol concentrations above 20 to 30 micrograms/L. Non-responders and good responders to chlorpromazine treatment, however, have plasma drug concentrations in the same range, and a therapeutic range of plasma chlorpromazine levels has not been defined. Therapeutic plasma haloperidol concentrations (i.e. 'window') in the range of 5 to 20 micrograms/L have been reported by some investigators, but others have found no such relationship.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Influence Of Blood-brain Distribution On Results Using Radiomentioning

confidence: 91%

Section: Thioridazine and Chlorpromazinementioning

confidence: 94%

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Plasma Level Monitoring of Antipsychotic Drugs Clinical Utility

Dahl

1986

Clinical Pharmacokinetics

145

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“…In work conducted by other investigators 7-hydroxy-CI'Z was the most potent CPZ metabolite in its ability to increase plasma prolactin levels subsequent to injection in male rats (Meltzer et al 1977), to bind to alpha-1 adrenergic receptors (Hals et al 1986), to increase the levels of homovanillic acid in rat striatum (Krieglstein et al 1980), and to block amphetamine-induced stereotyped behaviour in rats (La1 and Sourkes 1972). Moreover, 7-hydroxy-CPZ attains concentrations in the cerebral spinal fluid of psychiatric patients that are equal to CPZ (Alfredssen et al 1982). It has been demonstrated that patients responding favorably to CPZ therapy have higher plasma levels of 7-hydroxy-CPZ (Salialis et al 1973, Mackay et al 1974.…”

Section: Discussionmentioning

confidence: 98%

“…Thus specified patients may not demonstrate therapeutic benefit with a particular class of phenothiazine because in addition to inter-individual variations they could be essentially 'metabolic nonresponders' (Sakalis et al 1973, Mackay et al 1974, Perel and Manian 1977, Alfredssen et al 1982.…”

Section: Introductionmentioning

confidence: 99%

Correlation of activity of chlorpromazine and respective hydroxy, dimethoxy and sulphoxide analogues on dopamine, muscarinic, histamine and calmodulin sites of action

Palmer¹,

Blosser²,

McCreedy³

et al. 1988

Xenobiotica

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1. Chlorpromazine (CPZ) is a unique molecule which has many potential sites of action, as well as a propensity to be transformed into a host of metabolites possessing varying degrees of pharmacological and/or toxic reactions. This investigation examined the rank order of potency of CPZ and eight metabolic derivatives with respect to displacement of 3H-spiperone at central dopamine-2 (DA-2) receptors, 3H-pirenzepine at central muscarinic-1 (M-1) receptors, and inhibition of calmodulin-induced activation of cyclic AMP-dependent phosphodiesterase. 2. The most potent CPZ analogues to displace labelled spiperone from DA-2 receptors in rat striatum were: 3-hydroxy-CPZ, CPZ, 3,7-dihydroxy-CPZ, and 7-hydroxy-CPZ. Intermediate potency was observed with 8-hydroxy-CPZ, 3,7,8-trihydroxy-CPZ, and 7,8-dihydroxy-CPZ. Chlorpromazine sulphoxide and 7,8-dimethoxy-CPZ displayed the least activity at DA-2 receptors. 3. Displacement of labelled pirenzepine from M-1 receptors in rat frontal cortex occurred to the greatest extent with CPZ which was one to two orders of magnitude more potent than noted for 3-hydroxy-CPZ greater than 7-hydroxy-CPZ greater than CPZ-sulphoxide greater than 8-hydroxy-CPZ greater than 7,8-dimethoxy-CPZ. The least potent agents were 3,7-and 7,8-dihydroxy-CPZs and 3,7,8-trihydroxy-CPZ. 4. A partially purified calmodulin-sensitive preparation of cyclic AMP-dependent phosphodiesterase from guinea pig heart was most sensitive to inhibition by 7,8-dihydroxy-CPZ, 7,8-dimethoxy-CPZ, 3-hydroxy-CPZ, 7-hydroxy-CPZ, 8-hydroxy-CPZ and CPZ. Least inhibition occurred with 3,7-dihydroxy-CPZ, 3,7,8-trihydroxy-CPZ and CPZ-sulphoxide. 5. The DA-2 receptors were more sensitive to the active CPZ analogues than were the M-1 receptors while calmodulin-activated phosphodiesterase was the least sensitive preparation. 6. Comparisons of data were made with existing information from other laboratories and in general CPZ, 7-hydroxy-CPZ and 3-hydroxy-CPZ were the most potent compounds across different test conditions.

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