Evidence for Non-Linear Pharmacokinetics of Oxytocin in Anesthetizetized Rat

Eric Troncy1, Valérie Morin, Jérôme R.E. del Castillo, Simon Authier, Norma Ybarra, Colombe Otis, Dominique Gauvin, Jolanta Gutkowska

1Université de Montréal


Purpose: 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 (t½(λz) 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 t½(λz) 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. Conclusion: 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.

J Pharm Pharm Sci, 11 (4): 12-24, 2008

Full Text: