Pharmacokinetics of intravenous tramadol at two dose rates in awake and anaesthetized sheep

Sheep are animals widely used as experimental model for various surgical procedures. The need to find analgesic drugs which can be used in this species during the experimental procedures, sometimes also quite invasive, is thus imperative. Aim of the study is to assess the pharmacokinetic profile of tramadol (T) and its active metabolite O- desmethyltramadol (M1) after administration of T in awake and anaesthetized sheep. The study was approved by the animal welfare committee of the University of Padua (CEASA 80/2012). T at the dose of 4 (T4) and 6 (T6) mg/kg was administered by intravenous route in 6 healthy adult Brogna sheep according to a randomized crossover scheme (2x2), and in two groups (6 animals/group) of anaes- thetised sheep undergoing spinal surgery receiving T6 and T4 respectively (parallel design). At prefixed time points, plasma samples were collected in order to determine the concentrations of T and M1 by a validated HPLC-FL method (Giorgi et al., 2009). The pharmacokinetic analyses were performed by WinNonlin 5.3.1 according to bi- and non-compartmental model for T and M1, respectively. Plasma concentration vs time profiles of T and M1 were similar after the two doses in all treated sheep. In the anaesthetised sheep the concentrations of T were always higher than in awake animals. At the first time point after administration of T4 and T6, the concentration of T was 3.39 ± 0.21 and 4.60 ± 0.99 μg/mL in anaesthetized sheep, and 1.29 ± 0.17 μg/mL and 1.56 ± 0.10 μg/mL in the awake animals , respectively. The Clearance value was significantly smaller in anaesthetized than in awake sheep (2.49 ± 0.28 vs 4.86 ± 1.19 L/h/kg and 3.24 ± 0.39 vs 6.31 ± 0.95 L/h/kg following administration of T4 and T6, respectively) as well as the Vd (0.77 ± 0.15 vs 1.57 ± 1.15 L/kg and 0.73 ± 0.26 vs 2.87 ± 0.12 L/kg after T4 and T6 treatment, respectively). The AUC values in anaesthetized sheep were greater than those obtained in awake subjects (1.62 ± 0.18 vs 0.87 ± 0.24 μg/mL/h for T4 and 1.87 ± 0.21 vs 0.97 ± 0.14 μg/mL/h for T6). Concerning the pharmacokinetic parameters of M1, Cmax in anaesthetized and awake sheep was 0.09 ± 0.01 vs 0.14 ± 0.02 μg/mL following T4, and 0.10 ± 0.10 vs 0.16 ± 0.04 μg/mL after T6. The Tmax of M1 was delayed in sheep undergoing surgery if compared to awake subjects (0.98 ± 0.50 vs 0.37 ± 0.33 h and 0.58 ± 0.71 vs 0.40 ± 0.27 h for T4 and T6, respectively). The AUCM1/T ratios resulted equal to 0.22 and 0.25 in anaesthetized sheep and 0.36 and 0.43 in awake animals after administration of T4 and T6, respectively. The differences in pharmacokinetics parameters of T among anesthetized and awake sheep are probably due to the reduction of the cardiac output and hepatic blood flow that incur in anaesthetized animals. Buhari et al. (2013) reported similar findings in dogs. However, an influence of the anesthetic drugs on the pharma- cokinetic of T may not be excluded. The delay in the achievement of the Tmax of M1 in anaesthetized sheep might be due to the same reasons. The AUCM1/T ratios suggest a predominant metabolism of T in awake sheep. The reason of this difference is obscure but likely due to the presence of other drugs competing for the metabolization in anaesthetized sheep. Buhari et al., (2013) Asian J Anim Vet Adv 8, 483-492. Giorgi et al,. (2009) Vet Res Commun 33, 875-885.