Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue.
OBJECTIVE
Signal hyperintensity on unenhanced MRI in certain brain regions has been reported after multiple administrations of some, but not all, gadolinium-based contrast agents (GBCAs). One potential initial pathway of GBCA entry into the brain, infiltration from blood into the cerebrospinal fluid (CSF), was systematically evaluated in this preclinical study.


METHODS
GBCA infiltration and distribution in the CSF were investigated in healthy rats using repeated fluid-attenuated MRI up to 4 h after high-dose (1.8 mmol/kg) administration of six marketed and one experimental GBCA. Additionally, gadolinium measurements in CSF, blood and brain tissue samples (after 24 h) were performed using inductively coupled plasma mass spectrometry.


RESULTS
Enhanced MRI signals in the CSF spaces with similar distribution kinetics were observed for all GBCAs. No substantial differences in the gadolinium concentrations among the marketed GBCAs were found in the CSF, blood or brain tissue. After 4.5 h, the concentration in the CSF was clearly higher than in blood but was almost completely cleared and lower than the brain tissue concentration after 24 h.


CONCLUSIONS
In contrast to the brain signal hyperintensities, no differences in penetration and distribution into the CSF of healthy rats exist among the marketed GBCAs.


CONCLUSIONS
• Gadolinium-based contrast agents can cross the blood-CSF barrier. • Fluid-attenuated MRI shows GBCA distribution with CSF flow. • GBCA structure and physicochemical properties do not impact CSF penetration and distribution. • GBCA clearance from CSF was almost complete within 24 h in rats. • CSF is a potential pathway of GBCA entry into the brain.
MR and CT Contrast Media Research, Bayer Pharma AG, Muellerstrasse 178, 13353, Berlin, Germany. gregor.jost@bayer.com.
Gregor
G
Jost
MR and CT Contrast Media Research, Bayer Pharma AG, Muellerstrasse 178, 13353, Berlin, Germany.
Thomas
T
Frenzel
MR and CT Contrast Media Research, Bayer Pharma AG, Muellerstrasse 178, 13353, Berlin, Germany.
Jessica
J
Lohrke
Institute of Vegetative Physiology, Charité, Berlin, Germany.
Diana Constanze
DC
Lenhard
Department of Radiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Shinji
S
Naganawa
MR and CT Contrast Media Research, Bayer Pharma AG, Muellerstrasse 178, 13353, Berlin, Germany.
Hubertus
H
Pietsch
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D003287:Contrast Media / Q000493:pharmacokinetics; D005682:Gadolinium / Q000493:pharmacokinetics*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D013058:Mass Spectrometry; D023421:Models, Animal; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values
D003287:Contrast Media; D005682:Gadolinium
Brain; Cerebrospinal fluid; Contrast media; Gadolinium; Magnetic resonance imaging