title: Gastrointestinal delivery of propofol from fospropofol: its bioavailability and activity in rodents and human volunteers.
abstract: BACKGROUND
  Propofol is a safe and widely used intravenous anesthetic agent, for which additional clinical uses including treatment of migraine, nausea, pain and anxiety have been proposed (Vasileiou et al. Eur J Pharmacol 605:1-8, 2009). However, propofol suffers from several disadvantages as a therapeutic outside anesthesia including its limited aqueous solubility and negligible oral bioavailability. The purpose of the studies described here was to evaluate, in both animals and human volunteers, whether fospropofol (a water soluble phosphate ester prodrug of propofol) would provide higher propofol bioavailability through non-intravenous routes.
  
  
  METHODS
  Fospropofol was administered via intravenous, oral and intraduodenal routes to rats. Pharmacokinetic and pharmacodynamic parameters were then evaluated. Based on the promising animal data we subsequently conducted an oral and intraduodenal pharmacokinetic/pharmacodynamic study in human volunteers.
  
  
  RESULTS
  In rats, bioavailability of propofol from fospropofol delivered orally was found to be appreciable, in the order of around 20-70%, depending on dose. Availability was especially marked following fospropofol administration via the intraduodenal route, where bioavailability approximated 100%. Fospropofol itself was not appreciably bioavailable when administered by any route except for intravenous. Pharmacologic effect following oral fospropofol was confirmed by observation of sedation and alleviation of thermal hyperalgesia in the rat chronic constrictive injury model of neuropathic pain. The human data also showed systemic availability of propofol from fospropofol administration via oral routes, a hereto novel finding. Assessment of sedation in human volunteers was correlated with pharmacokinetic measurements.
  
  
  CONCLUSIONS
  These data suggest potential utility of oral administration of fospropofol for various therapeutic indications previously considered for propofol.
authors.affiliation: Eisai Inc., Baltimore, MD, USA. kwoznia3@jhmi.edu.|Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, The John G. Rangos, Sr. Building, 855 N. Wolfe Street, Baltimore, MD, 21205, USA. kwoznia3@jhmi.edu.
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Wozniak
authors.affiliation: Eisai Inc., Baltimore, MD, USA. jvornov1@jhmi.edu.|Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, The John G. Rangos, Sr. Building, 855 N. Wolfe Street, Baltimore, MD, 21205, USA. jvornov1@jhmi.edu.|Medpace, Cincinnati, OH, USA. jvornov1@jhmi.edu.
authors.forename: James J
authors.initials: JJ
authors.lastname: Vornov
authors.affiliation: Eisai Inc., Baltimore, MD, USA. Bipin.Mistry@fda.hhs.gov.|Center for Veterinary Medicine, FDA, Derwood, MD, USA. Bipin.Mistry@fda.hhs.gov.
authors.forename: Bipin M
authors.initials: BM
authors.lastname: Mistry
authors.affiliation: Eisai Inc., Baltimore, MD, USA. ywu58@jhmi.edu.|Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, The John G. Rangos, Sr. Building, 855 N. Wolfe Street, Baltimore, MD, 21205, USA. ywu58@jhmi.edu.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, The John G. Rangos, Sr. Building, 855 N. Wolfe Street, Baltimore, MD, 21205, USA. rrais2@jhmi.edu.|Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA. rrais2@jhmi.edu.
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.affiliation: Eisai Inc., Baltimore, MD, USA. bslusher@jhmi.edu.|Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, The John G. Rangos, Sr. Building, 855 N. Wolfe Street, Baltimore, MD, 21205, USA. bslusher@jhmi.edu.|Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA. bslusher@jhmi.edu.|Department of Psychiatry, and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA. bslusher@jhmi.edu.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D041981:Gastrointestinal Tract / Q000187:drug effects*; D064368:Healthy Volunteers; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D015742:Propofol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley; D055815:Young Adult
chemical_list: D000700:Analgesics; D006993:Hypnotics and Sedatives; C472965:fospropofol; D015742:Propofol