Pharmacokinetics of tramadol and O‐desmethyltramadol in healthy dogs after a single oral dose of 2 mg/kg

Tramadol exposure after low oral doses is variable in dogs, and the estimation of the terminal phase can be difficult when late concentrations plateau or rebound. This study characterized tramadol and O‐desmethyltramadol (M1) after a single oral dose of 2 mg/kg in 10 healthy female mixed‐breed dogs. Plasma was collected from 0 to 48 h and analysed by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Non‐compartmental analysis was performed for each animal. The terminal slope was evaluated using at least three quantifiable post‐peak observations, and λz was not forced when a coherent log‐linear decline was absent. Mean maximum observed concentration ( C max ) and area under the concentration–time curve from time zero to the last quantifiable concentration (AUC0–last) for tramadol were 434.53 ± 337.68 ng/mL and 1748.40 ± 1370.05 h·ng/mL, respectively; median time to maximum observed concentration ( T max ) was 1.5 h (range, 0.5–2.0 h). For M1, mean C max and AUC0–last were 6.53 ± 3.26 ng/mL and 34.86 ± 28.55 h·ng/mL, respectively; median T max was 1.0 h (0.5–2.0 h). A terminal phase was retained in seven of 10 profiles for each analyte. In these profiles, mean terminal half‐life was 15.53 ± 10.69 h for tramadol and 12.65 ± 11.55 h for M1. Three analyte profiles lacked a defensible terminal phase. We excluded quantitative pharmacokinetic analysis of M2 and M5 because authentic analytical standards were unavailable. Oral tramadol at 2 mg/kg was rapidly absorbed, but systemic exposure varied markedly among dogs. Based on the retained terminal half‐life estimates, a 12‐h dosing interval may be pharmacokinetically plausible for future multiple‐dose studies but should not be considered a validated clinical recommendation.