title: A pegylated growth hormone receptor antagonist, pegvisomant, does not enter the brain in humans.
abstract: 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.
authors.affiliation: 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
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
authors.forename: Martin
authors.initials: M
authors.lastname: Bidlingmaier
authors.forename: Joy
authors.initials: J
authors.lastname: Bailey
authors.forename: Dana
authors.initials: D
authors.lastname: Erickson
authors.forename: Paola
authors.initials: P
authors.lastname: Sandroni
mesh_terms: 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*
chemical_list: D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; C406545:pegvisomant
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