A pegylated growth hormone receptor antagonist, pegvisomant, does not enter the brain in humans.
BACKGROUND
GH receptors exist in the hippocampus, cerebral cortex, and hypothalamus, possibly influencing mood, cortical blood flow, and neuronal growth and mediating negative feedback.


BACKGROUND
Pegvisomant is a recombinant mutated GH molecule with high affinity, but little or no activating capability, for the GH receptor. It is used clinically as a GH antagonist.


OBJECTIVE
Systemic pegvisomant enters brain interstitial fluid via putative choroid-plexus GH receptors, thereby allowing for antagonism of central actions of GH. SUBJECTS AND LOCATION: Six adults requiring a cerebrospinal fluid (CSF) examination for nonneoplastic and noninflammatory syndromes participated at a tertiary medical center.


METHODS
Direct assays were conducted of serum and CSF pegvisomant concentrations 18-24 h after sc injection of pegvisomant (20 mg).


RESULTS
Median (range) concentrations of pegvisomant in serum were 215 (74-539) microg/liter and in CSF 0.035 (0.010-0.28) microg/liter (P=0.016). CSF drug levels were indistinguishable from assay threshold. Corresponding GH values were 0.29 (0.010-1.3) in serum and 0.075 microg/liter (0.01-0.13) in CSF. The geometric mean ratios of serum/CSF pegvisomant and GH concentrations were 5116:1 and 3.5:1, respectively, thus defining a more than 1400-fold difference between mutated and natural GH.


CONCLUSIONS
Based upon CSF measurements, a pegylated GH-receptor antagonist does not cross the human blood-brain barrier, thereby sparing inhibition of central nervous system GH actions. Thus, the capability of this antagonist to stimulate GH secretion predominantly reflects its actions outside the blood-brain barrier, such as via the median eminence and/or via suppression of IGF-I concentrations.
Veldhuis
Johannes D
JD
Endocrine Research Unit, Department of Neurology, Mayo School of Graduate Medical Education, Clinical Translation Research Center, Mayo Clinic, Rochester, Minnesota 55905, USA. veldhuis.johannes@mayo.edu
Bidlingmaier
Martin
M
Bailey
Joy
J
Erickson
Dana
D
Sandroni
Paola
P
D000368:Aged; D001812:Blood-Brain Barrier / Q000378:metabolism*; D005260:Female; D019382:Human Growth Hormone / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors*
D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; C406545:pegvisomant
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