Pharmacokinetics of tramadol and its metabolite M1 following intravenous administration of tramadol at two dosing rate in sheep undergoing spinal surgery

OBJECTIVE To assess the pharmacokinetics of tramadol (T) and its metabo- lite O-desmethyltramadol (M1) after IV administration of T in sheep undergoing experimental lumbar spine surgery.METHODS Twelve Brogna breed, approximately 3-year-old, female sheep were equally/randomly divided into two groups. Once the tar- get level of general anaesthesia was achieved, 4 or 6 mg kg 1 T, were IV administered. Blood samples were collected at scheduled times (0, 5, 15, 30, 45, 60, 90, 120, 240 and 300 min). T and M1 quantification in plasma was carried out by a HPLC validated method. The pharmacokinetic analysis was performed by WinNonlin 5.3. RESULTS Pharmacokinetic parameters of T and M1 were determined by a bi-compartmental and non-compartmental analysis, respec- tively. The plasma concentrations of T after administration of both doses dropped down rapidly. T was detectable in all the sheep up to 2 h from the drug administration. After adminis- tration of 4 and 6 mg kg 1 of T, the main parameters of the parental drug were: T1/2elim0.99 ` 0.46 and 0.68 ` 0.20 h; Cl 2.49 ` 0.28 and 3.24 ` 0.39 l h 1 kg 1; Vd 772.72 ` 149.47 ml kg 1 and 734.36 ` 265.53 ml kg 1, respectively. M1was found in all the animals but its concentra- tions were very low. The Cmax was 0.09 ` 0.04 and 0.10 ` 0.10 lg ml 1 achieved at Tmax of 0.98 ` 0.50 and 0.58 ` 0.71 h after administration low and high dose of T, respectively. DISCUSSION AND CONCLUSIONS After the administration of the two doses of T, the concentra- tion versus time curves of T and M1, were similar. An earlier study (Bortolami et al., submitted) where non-anesthetized sheep received T at 4 and 6 mg kg 1 showed lower concentra- tions of the parental drug than those reported in the present study. The diverse value of clearance (smaller in the present study) seemed to trigger this difference. It might be due to the blood flow modification that occurs during anesthesia. This is in line with the findings reported in a former pharmacokinetic study in anesthetized/non-anesthetized dogs (Buhari et al., 2013). In the present study, the AUCM1/T ratio after the low dose was similar to that obtained with high dose, suggesting that T metabolism is not dissimilar (saturated) at 4 and 6 mg kg 1. Further studies are warranted to establish the efficacious blood concentration of T and M1 in sheep. REFERENCES 1. Bortolami E., della Rocca G., Di Salvo A., Giorgi M., Kim T.W., Isola M., De Benedictis G.M. (submitted). Pharmacoki- netics and antinociceptive effects of tramadol and its metab- olite M1 following intravenous administration in sheep. The Veterinary Journal (submitted) 2. Buhari S., Kalthum H., Goh Y.M., Gan S.H. (2013). Influ- ence of surgery on the pharmacokinetics of tramadol follow- ing intravenous administration in dogs. Asian Journal of Animal and Veterinary Advances, 8, 483–492.