Dose-dependent and time-dependent pharmacokinetics in the dog after intravenous administration of dextrorphan

The disposition of dextrorphan after single ascending iv doses and multiple iv dosing regimens was studied in Marshall beagle dogs. A dose-dependent decrease in plasma clearance was observed after the administration of single iv doses of 0.88 mg/kg, 2.64 mg/kg, and 8.8 mg/kg of dextrorphan (i.e. mean plasma clearance values +/- SD were 100 +/- 25 vs. 68 +/- 28 vs. 48 +/- 20 ml/min.kg, respectively; p less than 0.001). Upon multiple dosing, the plasma clearance of dextrorphan increased in a time-dependent fashion for the two highest doses, approaching values observed for the 0.88 mg/kg/day iv dosing regimen. Female dogs exhibited a greater increase in plasma clearance with time. For all dogs, however, dextrorphan plasma clearance approached or exceeded hepatic plasma flow rate, suggesting the possibility of extrahepatic metabolism or elimination. Modest dose- and time-dependent changes in the steady-state volume of distribution of dextrorphan also were observed. The AUC of the conjugated metabolites of dextrorphan decreased in a time-dependent manner for the 8.8 mg/kg/day dosing regimen. The nonlinear kinetics of dextrorphan after iv administration appeared to occur only after potentially toxic dosing regimens of dextrorphan hydrochloride. We postulate mechanisms to explain the dose- and time-dependent kinetics of dextrorphan observed in the beagle dog.