title: Evidence for non-linear pharmacokinetics of oxytocin in anesthetizetized rat.
abstract: OBJECTIVE
  Because oxytocin (OT) is potentially useful in cardiovascular therapy but has hormonal roles on the cardiovascular and renal systems, we characterized its pharmacokinetic (PK) properties as a function of dose.
  
  
  METHODS
  A single intravenous bolus of OT was given at doses of 200, 300, 500, 1000, 3000, 5000 and 10000 ng/kg to anesthetized male rats (n >= 4 per dose). Blood samples (6) were taken over 72 min to 150 min, depending on dose. The individual time-courses of plasma OT concentrations were analyzed with a one- or an open two-compartment PK model. Kruskal-Wallis tests (alpha=0.05) were used to compare the PK parameters among groups.
  
  
  RESULTS
  At doses up to 500 ng/kg, OT showed a higher median systemic clearance (CLT = 0.0624 L/(min*kg); 0.0622 +/- 0.0228 as mean +/- SD value), a higher median central compartment volume of distribution (VC = 0.7906 L/kg; 0.6961 +/- 0.1754), and a lower median elimination half life (t(1/2)(lambdaz) 7.94 min; 9.08 +/- 4.3) with respect to the higher doses (CLT = 0.0266 L/(min*kg); 0.0284 +/- 0.0098, VC = 0.2213 L/kg; 0.2227 +/- 0.1142, and t(1/2)(lambdaz) 21.09 min; 28.36 +/- 21.8), all differences being significant (p 0.0008). Minimal differences were found for the estimates of these PK parameters among the 4 higher OT doses.
  
  
  CONCLUSIONS
  The PK properties and persistence of exogenous OT are not proportional to dose, therefore this must be accounted for in dosing regimen design for potential cardiovascular therapy.
authors.affiliation: 1GREPAQ (Groupe de recherche en pharmacologie animale du Québec), Department of veterinary biomedicine, Faculty of veterinary medicine, Université de Montréal, St-Hyacinthe, Quebec.
authors.forename: Valérie
authors.initials: V
authors.lastname: Morin
authors.forename: Jérôme R E
authors.initials: JR
authors.lastname: Del Castillo
authors.forename: Simon
authors.initials: S
authors.lastname: Authier
authors.forename: Norma
authors.initials: N
authors.lastname: Ybarra
authors.forename: Colombe
authors.initials: C
authors.lastname: Otis
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauvin
authors.forename: Jolanta
authors.initials: J
authors.lastname: Gutkowska
authors.forename: Eric
authors.initials: E
authors.lastname: Troncy
mesh_terms: D000758:Anesthesia; D000818:Animals; D004333:Drug Administration Routes; D007275:Injections, Intravenous; D008297:Male; D017711:Nonlinear Dynamics; D010121:Oxytocin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000502:physiology*
chemical_list: D010121:Oxytocin