title: Pharmacokinetic and pharmacodynamic modelling of intravenous, intramuscular and subcutaneous buprenorphine in conscious cats.
abstract: OBJECTIVE
  To describe simultaneous pharmacokinetics (PK) and thermal antinociception after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (SC) buprenorphine in cats.
  
  
  METHODS
  Randomized, prospective, blinded, three period crossover experiment.
  
  
  METHODS
  Six healthy adult cats weighing 4.1±0.5 kg.
  
  
  METHODS
  Buprenorphine (0.02 mg kg(-1)) was administered i.v., i.m. or s.c.. Thermal threshold (TT) testing and blood collection were conducted simultaneously at baseline and at predetermined time points up to 24 hours after administration. Buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. TT was analyzed using anova (p<0.05). A pharmacokinetic-pharmacodynamic (PK-PD) model of the i.v. data was described using a model combining biophase equilibration and receptor association-dissociation kinetics.
  
  
  RESULTS
  TT increased above baseline from 15 to 480 minutes and at 30 and 60 minutes after i.v. and i.m. administration, respectively (p<0.05). Maximum increase in TT (mean±SD) was 9.3±4.9°C at 60 minutes (i.v.), 4.6±2.8°C at 45 minutes (i.m.) and 1.9±1.9°C at 60 minutes (s.c.). TT was significantly higher at 15, 60, 120 and 180 minutes, and at 15, 30, 45, 60 and 120 minutes after i.v. administration compared to i.m. and s.c., respectively. I.v. and i.m. buprenorphine concentration-time data decreased curvilinearly. S.c. PK could not be modeled due to erratic absorption and disposition. I.v. buprenorphine disposition was similar to published data. The PK-PD model showed an onset delay mainly attributable to slow biophase equilibration (t(1/2) k(e0)=47.4 minutes) and receptor binding (k(on)=0.011 mL ng(-1) minute(-1)). Persistence of thermal antinociception was due to slow receptor dissociation (t(1/2) k(off)=18.2 minutes).
  
  
  CONCLUSIONS
  I.v. and i.m. data followed classical disposition and elimination in most cats. Plasma concentrations after i.v. administration were associated with antinociceptive effect in a PK-PD model including negative hysteresis. At the doses administered, the i.v. route should be preferred over the i.m. and s.c. routes when buprenorphine is administered to cats.
authors.affiliation: Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, Sao Paulo State University, UNESP Botucatu, São Paulo, Brazil. psteagall@gmail.com
authors.forename: Paulo V M
authors.initials: PV
authors.lastname: Steagall
authors.forename: Ludovic
authors.initials: L
authors.lastname: Pelligand
authors.forename: Tatiana
authors.initials: T
authors.lastname: Giordano
authors.forename: Christophe
authors.initials: C
authors.lastname: Auberger
authors.forename: John W
authors.initials: JW
authors.lastname: Sear
authors.forename: Stelio P L
authors.initials: SP
authors.lastname: Luna
authors.forename: Polly M
authors.initials: PM
authors.lastname: Taylor
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D002047:Buprenorphine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D002415:Cats; D018592:Cross-Over Studies; D005260:Female; D007273:Injections, Intramuscular / Q000662:veterinary; D007275:Injections, Intravenous / Q000662:veterinary; D007279:Injections, Subcutaneous / Q000662:veterinary; D008297:Male
chemical_list: D000701:Analgesics, Opioid; D002047:Buprenorphine