(19)F magnetic resonance spectroscopy as a tool to study clinical pharmacokinetics: Fluvoxamine in the treatment of obsessive compulsive disorder

摘要

Fluorine magnetic resonance spectroscopy ($sp{19}$F MRS) provides a unique tool for non-invasive, serial measurements of the concentration of fluorinated, psychotropic medications in human brain. Fluvoxamine is a trifluorinated selective serotonin reuptake inhibitor in world wide usage for a variety of psychiatric illnesses. $sp{19}$F MRS can be used to quantify the concentration of fluvoxamine in brain down to the nanomole/ml range because of the high sensitivity of fluorine to magnetic fields and the absence of significant endogenous mobile phase fluorine in the body. The specific aim of this work was to characterize the uptake, steady-state, and elimination phases of fluvoxamine treatment in brain and model the disposition of fluvoxamine in the body.;A specialized fluorine data acquisition system was designed to function with the standard clinical magnetic resonance scanner in our laboratory. The fluorine coil was an elliptical, sixteen leg, short bore, birdcage design with a copper backplane to achieve optimal sample coupling and field homogeneity. Subjects for a fluvoxamine uptake and steady-state study and a drug withdrawal study were recruited from the Center for Anxiety and Depression at the University of Washington. Subjects underwent serial $sp{19}$F MRS scanning during inception and maintenance or withdrawal of fluvoxamine treatment to determine the time course of whole brain drug levels. Whole blood samples were taken at each session to measure plasma fluvoxamine concentration.;Fluvoxamine was found to attain steady-state in brain more slowly than in plasma. The biological half-life of brain fluvoxamine was about 58 hours, 2 to 3 times longer than the plasma half-life. The brain-to-plasma ratio of fluvoxamine concentration at steady-state was 26 to 1. The dissociation between the brain and plasma time course implies that fluvoxamine distribution is multi-compartmental. An improved calculation scheme was developed to allow determination of the compartmental parameters from the $sp{19}$F MRS data. The volume of distribution of the peripheral compartment was 1.12 L/Kg. This indicates that fluvoxamine is highly bound in brain tissue. This work represents an advance in the ability to perform quantitative, non-invasive pharmacokinetic studies of psychoactive compounds in the central nervous system.