Dopaminergic D2 receptor binding of phenothiazine drugs and their metabolites

Hals, Petter‐Arnt; Dahl, Svein G.

doi:10.3109/08039488409093396

“…These metabolites seem to be devoid of pharmacological activity (Hals & Dahl 1984). Preliminary results indicate that the disposition of perphenazine is related to polymorphic debrisoquine hydroxylation (Dahl-Puustinen et al 1989).…”

Section: Perphenazinementioning

confidence: 94%

Pharmacokinetic Optimisation of the Treatment of Psychosis

Balant-Gorgia¹,

Balant

²

,

Andréoli³

1993

Clinical Pharmacokinetics

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Psychosis is a generic term covering (for the purposes of the present article)) schizophrenia, brief reactive psychoses and manic episodes. Traditionally, research has focused on the effect of antipsychotic agents on positive or productive symptoms such as hallucinations or delusions. More recently, attention has been focused on negative symptoms such as emotional withdrawal or impairment of social participation. Typical antipsychotic medications such as phenothiazines have little effect on these clinical manifestations. This has raised interest in atypical antipsychotics such as clozapine. Acute psychotic episodes are less difficult to treat than long term schizophrenic manifestations. Current research indicates that antipsychotics are effective only if a threshold concentration is reached, but that above a certain level, dose escalation is of no benefit to the patient. This implies the existence of an optimal therapeutic concentration range. Due to interindividual variability caused by age, genetic and interethnic factors or drug-drug interactions, antipsychotic plasma concentrations show a wide range of values for the same dosage regimen. This is why clinical pharmacokinetic principles and therapeutic drug monitoring are essential tools for dosage individualization. Clinical pharmacokinetics in therapeutics implies that the pharmacokinetic parameters of the medication under scrutiny are known. This is, however, not always the case with antipsychotics since, due to the difficulties encountered in conducting phase I studies in healthy volunteers with these substances, published data are not always complete.

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“…FLUPHENAZINE N 4 '-0XIDE kawa 1980; Lewis et al 1983, Hals and Dahl 1984, Morel et al 1987. Accordingly, these metabolites of FLU may contribute to its pharmacologic effects by interactions at dopaminergic or other brain receptors such as the 5HT2, and 01-adrenergic receptors.…”

Section: Fluphenazine (Flu)mentioning

confidence: 99%

Distribution of Fluphenazine and Its Metabolites in Brain Regions and Other Tissues of the Rat

Aravagiri

¹

,

Marder

²

,

Yuwiler

³

et al. 1995

Neuropsychopharmacology

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Rats were given 5, 10, or 20 mg/kg oral doses of fluphenazine (FLU) dihydrochloride daily for 15 days. FLU and its sulfoxide (FL-SO), 7-hydroxy (7-OH-FLU) and N4'-oxide (FLU-NO) metabolites were assayed in plasma, liver, kidney, fat, whole brain, and brain regions by specific and sensitive radioimmunoassays (RIA). All metabolites were detected in tissues at higher levels than in plasma, and the levels increased with dose. FLU was 10- to 27-fold higher in brain regions than in plasma. Brain vs plasma levels of FLU correlated more closely than levels of its metabolites. Liver contained the highest levels of all analytes at all doses. FLU-SO was the major metabolite in brain regions (24% to 96% of FLU) and accumulated in fat 43 to 75 times more than FLU. Levels of 7-OH-FLU and FLU-NO were very low in brain (1% to 20% of FLU). FLU-SO and FLU-NO had only 1% to 3% the affinity for D1 and D2 receptors, but 7-OH-FLU had 20% the D2 and 5% the D1 affinity of FLU. The low affinity for dopamine receptors and low brain-levels of metabolites of FLU indicate that they are not likely to contribute importantly to pharmacologic responses of FLU. Also, the estimated relative "activity factor" for these compounds in the brain indicated that the contribution to neuropharmacologic activity by metabolites is less than 1% of FLU. Consequently, clinical monitoring of plasma FLU alone may be sufficient.

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“…The sulfoxide (FLU-SO), N 4 '-oxide (FLU-NO) and 7-hydroxy (7-OH-FLU) metabolites of FLU ( Figure 1) are found in substantial levels in the plasma of patients treated with PO or IM preparations of FLU (Marder et al 1989). FLU-SO, FLU-NO, and 7-OH-FLU have been reported to have antidopaminergic activity themselves, with 7-OH-FLU metabolite being the most potent among them (Yamada and Furu- Lewis et al 1983, Hals and Dahl 1984, Morel et al 1987. Accordingly, these metabolites of FLU may contribute to its pharmacologic effects by interactions at dopaminergic or other brain receptors such as the 5HT2, and 01-adrenergic receptors.…”

mentioning

confidence: 99%

Distribution of Fluphenazine and Its Metabolites in Brain Regions and Other Tissues of the Rat

Aravagiri

¹

,

Marder

²

,

Yuwiler

³

et al. 1995

Neuropsychopharmacology

View full text Add to dashboard Cite

Rats were given 5, 10, or 20 mg/kg oral doses of fluphenazine (FLU) dihydrochloride daily for 15 days. FLU and its sulfoxide (FL-SO), 7-hydroxy (7-OH-FLU) and N4'-oxide (FLU-NO) metabolites were assayed in plasma, liver, kidney, fat, whole brain, and brain regions by specific and sensitive radioimmunoassays (RIA). All metabolites were detected in tissues at higher levels than in plasma, and the levels increased with dose. FLU was 10- to 27-fold higher in brain regions than in plasma. Brain vs plasma levels of FLU correlated more closely than levels of its metabolites. Liver contained the highest levels of all analytes at all doses. FLU-SO was the major metabolite in brain regions (24% to 96% of FLU) and accumulated in fat 43 to 75 times more than FLU. Levels of 7-OH-FLU and FLU-NO were very low in brain (1% to 20% of FLU). FLU-SO and FLU-NO had only 1% to 3% the affinity for D1 and D2 receptors, but 7-OH-FLU had 20% the D2 and 5% the D1 affinity of FLU. The low affinity for dopamine receptors and low brain-levels of metabolites of FLU indicate that they are not likely to contribute importantly to pharmacologic responses of FLU. Also, the estimated relative "activity factor" for these compounds in the brain indicated that the contribution to neuropharmacologic activity by metabolites is less than 1% of FLU. Consequently, clinical monitoring of plasma FLU alone may be sufficient.

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Dopaminergic D2 receptor binding of phenothiazine drugs and their metabolites

Cited by 5 publications

References 10 publications

Pharmacokinetic Optimisation of the Treatment of Psychosis

Pharmacokinetic Optimisation of the Treatment of Psychosis

Distribution of Fluphenazine and Its Metabolites in Brain Regions and Other Tissues of the Rat

Distribution of Fluphenazine and Its Metabolites in Brain Regions and Other Tissues of the Rat

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