title: The pharmacokinetics of acyl, des-acyl, and total ghrelin in healthy human subjects.
abstract: BACKGROUND
  Ghrelin stimulates GH secretion and regulates energy and glucose metabolism. The two circulating isoforms, acyl (AG) and des-acyl (DAG) ghrelin, have distinct metabolic effects and are under active investigation for their therapeutic potentials. However, there is only limited data on the pharmacokinetics of AG and DAG.
  
  
  OBJECTIVE
  To evaluate key pharmacokinetic parameters of AG, DAG, and total ghrelin in healthy men and women.
  
  
  METHODS
  In study 1, AG (1, 3, and 5 μg/kg per h) was infused over 65 min in 12 healthy (8 F/4 M) subjects in randomized order. In study 2, AG (1 μg/kg per h), DAG (4 μg/kg per h), or both were infused over 210 min in ten healthy individuals (5 F/5 M). Plasma AG and DAG were measured using specific two-site ELISAs (study 1 and 2), and total ghrelin with a commercial RIA (study 1). Pharmacokinetic parameters were estimated by non-compartmental analysis.
  
  
  RESULTS
  After the 1, 3, and 5 μg/kg per h doses of AG, there was a dose-dependent increase in the maximum concentration (C(max)) and area under the curve (AUC(0-last)) of AG and total ghrelin. Among the different AG doses, there was no difference in the elimination half-life, systemic clearance (CL), and volume of distribution. DAG had decreased CL relative to AG. The plasma DAG:AG ratio was ~2:1 during steady-state infusion of AG. Infusion of AG caused an increase in DAG, but DAG administration did not change plasma AG. Ghrelin administration did not affect plasma acylase activity.
  
  
  CONCLUSIONS
  The pharmacokinetics of AG and total ghrelin appears to be linear and proportional in the dose range tested. AG and DAG have very distinct metabolic fates in the circulation. There is deacylation of AG in the plasma but no evidence of acylation.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45219-0547, USA. jenny.tong@uc.edu
authors.forename: Jenny
authors.initials: J
authors.lastname: Tong
authors.forename: Nimita
authors.initials: N
authors.lastname: Dave
authors.forename: Ganesh M
authors.initials: GM
authors.lastname: Mugundu
authors.forename: Harold W
authors.initials: HW
authors.lastname: Davis
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gaylinn
authors.forename: Michael O
authors.initials: MO
authors.lastname: Thorner
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: David
authors.initials: D
authors.lastname: D'Alessio
authors.forename: Pankaj B
authors.initials: PB
authors.lastname: Desai
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D054439:Ghrelin / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D054439:Ghrelin; C422650:ghrelin, des-n-octanoyl