Methods for study of fluphenazine kinetics in man

Area of Science:

• Pharmacology
• Analytical Chemistry
• Clinical Pharmacy

Background:

• Fluphenazine is an antipsychotic medication requiring understanding of its metabolic fate.
• Accurate quantification of fluphenazine and its metabolites is crucial for therapeutic drug monitoring.
• Previous methods for assessing drug kinetics could be invasive or complex.

Purpose of the Study:

• To identify and quantify fluphenazine and its primary metabolites in human biological matrices.
• To investigate the pharmacokinetic profile of fluphenazine following different administration routes.
• To establish a non-radioactive method for assessing fluphenazine kinetics using urinary excretion.

Main Methods:

• Radioactive 14C-fluphenazine dihydrochloride administered orally and intramuscularly.
• Extraction techniques including n-heptane for unmetabolized fluphenazine and toluene for metabolites.
• Hydrolysis of conjugates to quantify parent drug and metabolites in plasma, urine, and feces.
• Analysis of fluphenazine and conjugates in urine from patients on long-term fluphenazine decanoate therapy.

Main Results:

• Fluphenazine, fluphenazine sulphoxide, and 7-hydroxyfluphenazine were identified and quantified.
• A significant conjugate fraction was observed in all biological samples.
• Urinary excretion rate of conjugates correlated with plasma concentration, independent of urine flow or pH.
• These findings were consistent in both acute (radioactive) and chronic (non-radioactive) therapy studies.

Conclusions:

• Fluphenazine undergoes significant metabolism to sulphoxide and hydroxylated forms, with conjugation occurring.
• Urinary excretion of fluphenazine conjugates provides a practical and reliable method for assessing fluphenazine pharmacokinetics.
• This non-radioactive urinary excretion method simplifies therapeutic drug monitoring for fluphenazine therapy.