Radioimmunoassay for the 7-Hydroxy Metabolite of Trifluoperazine and its Application to a Kinetic Study in Human Volunteers

Aravagiri, Manickam; Hawes, E. M.; Midha, K. K.

doi:10.1002/jps.2600741113

“…The antibodies used in the RIAs of FLU-SO, 7-OH-FLU, and FLU-NO were polyclonal antibodies raised against suitable trifluoperazine sulfoxide, trifluoperazine 7-hydroxy, and prochlorperazine N 4 '-oxide hapten-BSA conjugate based immunogens in New Zealand white rabbits (Aravagiri et al 1984(Aravagiri et al , 1985(Aravagiri et al , 1986 The antibody used in the RIA of FLU was monoclonal and raised against a FLU hapten-thyroglobulin-based immunogen using hybridoma technique in mice as reported previously (McKay et al 1990).…”

Section: Antibodiesmentioning

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 antibodies used in the RIAs of FLU-SO, 7-OH-FLU, and FLU-NO were polyclonal antibodies raised against suitable trifluoperazine sulfoxide, trifluoperazine 7-hydroxy, and prochlorperazine N 4 '-oxide hapten-BSA conjugate based immunogens in New Zealand white rabbits (Aravagiri et al 1984(Aravagiri et al , 1985(Aravagiri et al , 1986 The antibody used in the RIA of FLU was monoclonal and raised against a FLU hapten-thyroglobulin-based immunogen using hybridoma technique in mice as reported previously ).…”

Section: Antibodiesmentioning

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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“…Recently, radioimmunoassays have been described for the measurement of the sulfoxide (Aravagiri et al 1984), N4-oxide (Aravagiri et al 1986), and 7-hydroxy (Aravagiri et al 1985) metabolites of trifluoperazine in plasma. Preliminary studies suggest that one of the causes of intersubject variation may relate to differences between individuals in Offprint requests to: K.K.…”

mentioning

confidence: 99%

“…Midha the extent of conversion of the parent drug into its sulfoxide (Aravagiri et al 1984) and N4-oxide (Aravagiri et al 1986) metabolites during the first passage through the gut wall, liver, and lung before entering the systemic circulation (presystemic absorption). The unconjugated 7-hydroxy metabolite appeared to be formed less extensively during presystemic absorption (Aravagiri et al 1985), but there was wide variation in the apparent elimination half-life and in the ratio of the area under the plasma concentration versus time curve (AUC) of the metabolite to that of the parent drug.…”

mentioning

confidence: 99%

A pharmacokinetic study of trifluoperazine in two ethnic populations

Midha

¹

,

Hawes

²

,

Hubbard

³

et al. 1988

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The single dose pharmacokinetics of trifluoperazine (5 mg, Stelazine) were investigated in black (n = 25) and white (n = 32) healthy male subjects. Plasma samples were harvested over 24 h and analysed by a GLC-MS method. There were wide intersubject variations in all pharmacokinetic parameters examined, including Cmax, AUC, apparent oral volume of distribution at steady state, and elimination half-life. For each of these parameters the distribution was positively skewed in both blacks and whites and the geometric mean gave a better estimate of central tendency than the corresponding arithmetic mean. In all pharmacokinetic parameters examined there was no significant difference detected between black and white subjects or between smokers and non-smokers.

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Radioimmunoassay for the 7-Hydroxy Metabolite of Trifluoperazine and its Application to a Kinetic Study in Human Volunteers

Cited by 11 publications

References 12 publications

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

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

A pharmacokinetic study of trifluoperazine in two ethnic populations

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