title: Pharmacokinetics and behavioral effects of liposomal hydromorphone suitable for perioperative use in rhesus macaques.
abstract: BACKGROUND
  This study aims to evaluate the pharmacokinetic, behavioral, and motor effects of a liposomal preparation of hydromorphone hydrochloride (LE-hydro) in rhesus monkeys. We administered either 2 mg/kg of LE-hydro (n = 8) subcutaneous (s.c.) or 0.1 mg/kg of standard pharmaceutical hydromorphone HCl (hydro) preparation either intravenous (i.v.; n = 4) or s.c. (n = 5).
  
  
  METHODS
  Serial blood samples were drawn after injection and analyzed for serum hydro concentration by liquid chromatography/mass spectrometry. Following s.c. injection of 0.1 mg/kg hydro or 2 mg/kg LE-hydro, behavioral evaluations were conducted in groups of rhesus monkeys (n = 10/group) in the presence of a compatible stimulus animal and motor skills were also evaluated (n = 10/group). The motor skills test consisted of removing a food reward (carrot ring) from either a straight peg (simple task) or a curved peg (difficult task).
  
  
  RESULTS
  LE-hydro (MRT(0-INF) = 105.9 h) demonstrated extended-release pharmacokinetics compared to hydro when administered by either i.v. (MRT(0-INF) =1.1 h) or s.c. (MRT(0-INF) =1.3 h) routes. Hydro did not affect motor performance of the simpler task, but the monkeys' performance deteriorated on the more difficult task at 0.5 and 1 h after injection. LE-hydro had no effect on motor skills in either the simpler or more difficult task.
  
  
  CONCLUSIONS
  The results of these studies indicate that LE-hydro has a pharmacokinetic and behavioral side effects profile consistent with an analgesic that could be tested for surgical use in animals. Our studies also expand the use of rhesus monkeys as a translational behavioral pharmacodynamics model for testing extended-release opioid medication.
authors.affiliation: Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53726-4089, USA. lisakh@rarc.wisc.edu
authors.forename: Lisa
authors.initials: L
authors.lastname: Krugner-Higby
authors.forename: Butch
authors.initials: B
authors.lastname: KuKanich
authors.forename: Brynn
authors.initials: B
authors.lastname: Schmidt
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Heath
authors.forename: Carolyn
authors.initials: C
authors.lastname: Brown
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002853:Chromatography, Liquid; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D005260:Female; D004091:Hydromorphone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008081:Liposomes; D008253:Macaca mulatta; D008297:Male; D013058:Mass Spectrometry; D009048:Motor Skills / Q000187:drug effects*; D012201:Reward
chemical_list: D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D008081:Liposomes; D004091:Hydromorphone