Brain Pharmacokinetics and Drug Studies

cover The University of Washington DISC has pioneered the development and clinical applications of 19F MRS for characterizing brain pharmacokinetics non-invasively in humans. The construction of dedicated 19F MRS head coils, both linear birdcage and quadrature coils, development of pulse sequences and new analytic approaches have allowed us to characterize brain uptake, steady-state, volume of distribution, the flux between bound and unbound drug pools, and brain elimination half-life of psychotropic drugs used to treat various psychiatric disorders in adults and children.

A number of medications, including anesthetic agents, chemotherapeutics and psychotropic agents, incorporate 19F as part of their native chemical structure. For example, 5 of 6 FDA-approved SSRI’S are fluorinated, thus allowing noninvasive quantification of brain drug levels. Prior work by our group had been to develop a two-compartment model for characterizing brain pharmacokinetics in humans. This model has been used to study the brain pharmacokinetics of antidepressants, including Prozac (fluoxetine) and Luvox (fluvoxamine), prescribed to treat various psychiatric conditions. Development and application of 19F magnetization transfer methods has allowed us to dynamically measure brain drug binding and the bound and unbound pool turnover for these commonly prescribed drugs. Subsequent work has investigated age-relationships to brain pharmacokinetics through studying both pediatric and adult populations taking commonly prescribed SSRI’s. These SSRI brain pharmacokinetic studies of children were the first undertaken and have substantial clinical and drug testing applications, particularly in the context of evolving FDA standards for pediatric drug testing.

coffe Additional work studying brain drug effects has investigated the brain metabolic effects of caffeine and how caffeine withdrawal modulates brain metabolic response to caffeine. Additionally, we have studied brain uptake of alcohol and dietary supplements, such as myo-inositol. More recent work has used fMRI to investigate brain activation patterns in response to drug craving/arousal in heroin addicts, before and after treatment with dialectric behavioral therapy.

 

 Publications:

  • Strauss WL, Unis AS, Cowan C, Dawson G, Dager SR:  19F Measurement of Brain Fluvoxamine and Fluoxetine in Pediatric Patients Treated for Pervasive Developmental Disorders.  Am J Psychiatry 159:755-760, 2002 (featured cover article with accompanying editorial)
  • Strauss WL, Dager SR: Magnetization Transfer of Fluoxetine in the Human Brain using 19 Fluorine Magnetic Resonance Spectroscopy.  Biol Psychiatry 4(9):790-802, 2001.

  • Dager SR, Friedman SD:  Brain Imaging and the Effects of Caffeine and Nicotine.  Annals of Medicine 32(90):592-599, 2000.

  • Dager SR, Layton ME, Strauss W, Friedman S, Richards TL, Heide A, Artru AA, Hayes C, Posse S:  Human Brain Metabolic Response to Caffeine and the Effects of Tolerance.  Am J Psychiatry 156(2):229-237, 1999 (featured cover article)
  • Moore CM, Breeze JL, Kukes TH, Rose SL, Dager SR, Cohen BM, Renshaw PR: Effects of Myo-Inositol Ingestion on Human Brain Myo-inositol Levels:  A Proton Magnetic Resonance Spectroscopic Imaging Study.  Biol Psychiatry 45:1197-1202, 1999.
  • Strauss WL, Layton ME, Dager SR:  Characterization of Human Brain Pharmacokinetics Using A Two Compartment Model.  Biol Psychiatry 45:1384-1388, 1999.
  • Strauss W, Layton M, Dager SR:  Brain Elimination Half-Life of Fluvoxamine Measured by 19F Magnetic Resonance Spectroscopy.  Am J Psychiatry 155(3):380-384, 1998.
  • Strauss W, Layton M, Hayes C, Dager SR: Preliminary Findings on the Time Course of Fluvoxamine Washout from the Human Brain Measured with Fluorine Magnetic Resonance Spectroscopy.  Psychopharmacology Bulletin 33(3):589-590, 1997.
  • Strauss W, Layton M, Hayes C, Dager SR:  19F MRS Investigation In Vivo of Acute and Steady-State Brain Fluvoxamine Levels in Obsessive-Compulsive Disorder.  Am J Psychiatry 154(4):516-522, 1997.

 

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