Measurement of human brain dexfenfluramine concentration by 19F magnetic resonance spectroscopy.
OBJECTIVE
The goals of this study were to quantitate the brain concentration of the anorectic drug dexfenfluramine (DF) in human subjects receiving clinical doses of DF and to determine whether human brain DF concentrations approach those reported to cause irreversible neurochemical changes in animals. Each subject's brain DF concentration was measured several times over an extended period of DF treatment to determine whether drug accumulation in the brain would plateau or continue to increase throughout the treatment period.


METHODS
Fluorine magnetic resonance spectroscopy (19F-MRS) was used to directly detect and quantitate brain levels of the fluorinated drug dexfenfluramine and its active metabolite dex-norfenfluramine (dNF). Patients received 15 mg dexfenfluramine BID for 90 days. 19F-MRS measurements were performed at baseline and at three times during the treatment period.


METHODS
Twelve women (age 38-54 years) who were obese, with body mass indices of 28. 4-37.4, but otherwise healthy.


RESULTS
The combined concentration of DF and nDF reached steady-state in the human brain after approximately 10 days of treatment. The steady-state brain concentration averaged approximately 4 microM and did not tend to increase significantly during the 90 day treatment period.


CONCLUSIONS
These results demonstrate that fluorinated drugs can be quantified using 19F MRS at concentrations below 10 microM in the human brain. The time-course data suggest that brain DF concentrations parallel DF plasma pharmacokinetics in humans. Measured brain dexfenfluramine/nor-dexfenfluramine concentrations were well below levels previously found to cause irreversible brain alterations in animals.
Christensen
J D
JD
Brain Imaging Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.
Yurgelun-Todd
D A
DA
Babb
S M
SM
Gruber
S A
SA
Cohen
B M
BM
Renshaw
P F
PF
D000328:Adult; D001067:Appetite Depressants / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism*; D020372:Dexfenfluramine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D005461:Fluorine; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism
D001067:Appetite Depressants; D005461:Fluorine; D020372:Dexfenfluramine