Pharmacokinetics of tramadol and its metabolite M1 following intravenous administration in sheep

Sheep are widely used for invasive biomedical research, but there are limited data surrounding administration of analgesic drugs to sheep. The aim of this study was to investigate the pharmacokinetics of tramadol and its metabolite M1 in sheep. Six healthy adult sheep were administered 4 (T4) and 6 mg kg-1 (T6) tramadol intravenously in a cross over design with a 2 week wash-out period between doses. Blood samples were collected at specific time points up to 24 hours after administration. Analytical determination of tramadol in plasma was performed as described by Giorgi et al. (2009). Pharmacokinetic analysis fitted a two-compartmental (tramadol) and a non-compartmental (M1) model. At the first time point, five minutes after T4 and T6 administration, tramadol concentrations were 1.29±0.17 and 1.56±0.10 µg ml-1 respectively; plasma levels decreased very quickly in T4 and T6, and were below the limit of quantification 6 hours after administration. Mean elimination half-life was 0.67±0.42 and 0.57±0.12 hours for T4 and T6 respectively. M1 time to maximum plasma concentration was 0.37±0.33 and 0.40±0.27 hours and maximum plasma concentration was 0.14±0.02 and 0.16±0.04 µg ml-1 for T4 and T6 respectively; M1 was detectable up to 4 hours post-administration in all animals. IV administration of T4 and T6 in sheep was associated with a rapid metabolism and short lasting presence of M1 in plasma. Further studies are warranted to assess the analgesic efficacy of tramadol in this species.